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1.
Molecules ; 26(19)2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34641286

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Isotretinoína/farmacologia , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Talidomida/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Regiões Promotoras Genéticas , Proteômica/métodos
2.
Chem Biol Interact ; 349: 109652, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520751

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for about 80-85% of total lung cancer cases. Identifying the molecular mechanisms of anti-tumor drugs is essential for improving therapeutic effects. Herein, we aim to investigate the role of thalidomide in the tumorigenicity of NSCLC. METHODS: The A549 xenograft nude mouse model was established to explore therapeutic effects of thalidomide. The expression of FGD5-AS1 was evaluated in carcinomatous and paracarcinomatous tissues from NSCLC patients as well as NSCLC cell lines. CCK-8 assay was performed to assess cell viability. The invasive capacity was examined using transwell assay. The tube formation assay was applied to determine cell angiogenesis. Flow cytometry was subjected to validate CD8+ T cell activity. The FGD5-AS1/miR-454-3p/ZEB1 regulatory network was analyzed using luciferase reporter, RIP and ChIP assays. RESULTS: Thalidomide reduced tumor growth and angiogenesis and increased CD8+ T cell ratio in a mouse model. Enhanced expression of FGD5-AS1 was positively correlated with the poor survival of NSCLC patients. Knockdown of FGD5-AS1 notably suppressed the proliferation, invasion and angiogenesis of cancer cells as well as the apoptosis of CD8+ T cells. Thalidomide targeted FGD5-AS1 to exert its anti-tumor activity in NSCLC. FGD5-AS1 acted as a sponge of miR-454-3p to upregulate ZEB1, thus increasing the expression of PD-L1 and VEGFA. Simultaneous overexpression of FGD5-AS1 and silencing of miR-454-3p reversed thalidomide-mediated anti-tumor effects in NSCLC. CONCLUSION: Thalidomide inhibits NSCLC angiogenesis and immune evasion via FGD5-AS1/miR-454-3p/ZEB1 axis-mediated regulation of VEGFA expression and PD-1/PD-L1 checkpoint.


Assuntos
Inibidores da Angiogênese/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Neovascularização Patológica/prevenção & controle , RNA Longo não Codificante/metabolismo , Talidomida/farmacologia , Evasão Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/imunologia
3.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361041

RESUMO

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6'-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Gliose/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Talidomida/análogos & derivados , Animais , Lesões Encefálicas Traumáticas/complicações , Cognição , Gliose/etiologia , Hipocampo/metabolismo , Fatores Imunológicos/farmacologia , Masculino , Memória , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Talidomida/farmacologia , Talidomida/uso terapêutico
4.
Biochem Biophys Res Commun ; 574: 104-109, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34455369

RESUMO

Immunomodulatory imide drugs (IMiDs), such as lenalidomide and pomalidomide, exert pleiotropic effects, e.g., antitumor effects in multiple myeloma, by binding the protein Cereblon and altering its substrate specificity. Lenalidomide is approved for the treatment of adult T-cell leukemia/lymphoma (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1), although the precise mechanisms responsible for its effectiveness have not been fully elucidated. Here, we used HTLV-1-infected cell lines to investigate how IMiDs exert anti-ATL effects. In three of four tested HTLV-1-infected cell lines, the cells treated with lenalidomide or pomalidomide exhibited mild growth suppression without apoptosis, which was associated with decreased IRF4, c-Myc, and phosphorylated STAT3 levels as well as enhanced SOCS3 expression. Additionally, the levels of enhancer of zeste homolog 2 (EZH2) and trimethyl histone 3 Lys27 (H3K27me3) were decreased following IMiD treatment in all three susceptible cell lines. An IMiD-mediated reduction of EZH2 and H3K27me3 levels was also observed in a multiple myeloma cell line. Furthermore, treatment with an EZH2-inhibitor reproduced the IMiD-mediated effects in HTLV-1-infected cells and multiple myeloma cells. These findings strongly suggest that a reduction of EZH2 expression is involved in the mechanism underlying the antitumor effects of IMiD.


Assuntos
Antivirais/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Infecções por HTLV-I/tratamento farmacológico , Vírus Linfotrópico T Tipo 1 Humano/efeitos dos fármacos , Lenalidomida/farmacologia , Talidomida/análogos & derivados , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Infecções por HTLV-I/patologia , Humanos , Testes de Sensibilidade Microbiana , Talidomida/farmacologia
5.
J Med Chem ; 64(16): 12273-12285, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34378936

RESUMO

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform for the targeted delivery of IMiD-based molecular glues and PROTACs to FOLR1-expressing cancer cells with the potential to ameliorate toxicity.


Assuntos
Ácido Fólico/análogos & derivados , Ácido Fólico/farmacologia , Fatores Imunológicos/farmacologia , Pró-Fármacos/farmacologia , Proteólise/efeitos dos fármacos , Talidomida/análogos & derivados , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptor 1 de Folato/metabolismo , Células HEK293 , Humanos , Fator de Transcrição Ikaros/metabolismo , Fatores Imunológicos/síntese química , Proteínas de Fusão Oncogênica/metabolismo , Pró-Fármacos/síntese química , Proteínas Tirosina Quinases/metabolismo , Talidomida/síntese química , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/metabolismo
6.
Biochem Pharmacol ; 192: 114727, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390739

RESUMO

Thalidomide is an antiinflammatory, antiangiogenic and immunomodulatory agent which has been used for the treatment of erythema nodosum leprosum and multiple myeloma. It has also been employed in treating complex regional pain syndromes. The current study aimed to reveal the molecular mechanisms underlying thalidomide-induced pain antihypersensitive effects in neuropathic pain. Thalidomide gavage, but not its more potent analogs lenalidomide and pomalidomide, inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain rats induced by tight ligation of spinal nerves, with ED50 values of 44.9 and 23.5 mg/kg, and Emax values of 74% and 84% MPE respectively. Intrathecal injection of thalidomide also inhibited mechanical allodynia and thermal hyperalgesia in neuropathic pain. Treatment with thalidomide, lenalidomide and pomalidomide reduced peripheral nerve injury-induced proinflammatory cytokines (TNFα, IL-1ß and IL-6) in the ipsilateral spinal cords of neuropathic rats and LPS-treated primary microglial cells. In contrast, treatment with thalidomide, but not lenalidomide or pomalidomide, stimulated spinal expressions of IL-10 and ß-endorphin in neuropathic rats. Particularly, thalidomide specifically stimulated IL-10 and ß-endorphin expressions in microglia but not astrocytes or neurons. Furthermore, pretreatment with the IL-10 antibody blocked upregulation of ß-endorphin in neuropathic rats and cultured microglial cells, whereas it did not restore thalidomide-induced downregulation of proinflammatory cytokine expression. Importantly, pretreatment with intrathecal injection of the microglial metabolic inhibitor minocycline, IL-10 antibody, ß-endorphin antiserum, and preferred or selective µ-opioid receptor antagonist naloxone or CTAP entirely blocked thalidomide gavage-induced mechanical antiallodynia. Our results demonstrate that thalidomide, but not lenalidomide or pomalidomide, alleviates neuropathic pain, which is mediated by upregulation of spinal microglial IL-10/ß-endorphin expression, rather than downregulation of TNFα expression.


Assuntos
Interleucina-10/biossíntese , Microglia/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Talidomida/uso terapêutico , beta-Endorfina/biossíntese , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interleucina-10/agonistas , Masculino , Microglia/efeitos dos fármacos , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Talidomida/farmacologia , beta-Endorfina/agonistas
7.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299320

RESUMO

Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Neovascularização Patológica/induzido quimicamente , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Fluoruracila/metabolismo , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Paclitaxel/farmacologia , Neoplasias Gástricas/patologia , Talidomida/farmacologia , Timidina Fosforilase/genética , Regulação para Cima/efeitos dos fármacos
8.
Phys Chem Chem Phys ; 23(24): 13705-13713, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34128013

RESUMO

Thalidomide is a drug that presents two enantiomers with markedly different pharmacological and toxicological activities. It is sadly famous due to its teratogenic effects mostly caused by the preferential docking of the (S)-enantiomer to the target protein cereblon (CRBN). To compare the structure of the bound CRBN thalidomide enantiomers with that of the isolated molecule, the rotational spectrum of laser-ablated thalidomide has been studied by chirp-pulsed Fourier transform microwave spectroscopy in supersonic jets complemented by theoretical computations. A new setup of the laser ablation nozzle used is presented. Two stable equatorial and axial conformers of thalidomide have been predicted corresponding to the two possible bent conformations exhibited by the glutarimide moiety. Only the most stable equatorial conformer has been detected. The comparison of its structure with those of the (S)- and (R)-enantiomers bound to CBRN shows that the bound (S) species is only slightly distorted. On the contrary, the bound (R)-enantiomer exhibits a highly distorted structure which affects the degree of puckering of the glutarimide ring and especially to the orientation of the phtalimide and glutarimide subunits. This is consistent with a less stable (R)-enantiomer and the known preference of (S)-thalidomide to bind CRBN, which starts the process leading to teratogenic effects.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Lasers , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Conformação Molecular , Rotação , Estereoisomerismo , Talidomida/química , Talidomida/isolamento & purificação , Ubiquitina-Proteína Ligases/metabolismo
9.
Life Sci ; 281: 119771, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186051

RESUMO

AIMS: Medical treatment for lower urinary tract symptoms secondary to benign prostatic hyperplasia is characterized by an unfavorable balance between limited efficacy and pronounced side effects. We recently reported, that thalidomide reduces prostate smooth muscle contraction and inhibits cell growth. Like thalidomide, its analogs lenalidomide and pomalidomide are also in clinical use. Therefore, we investigated the effects of lenalidomide and pomalidomide on human prostate smooth muscle contraction, cytoskeletal organization, and growth-related functions in stromal cells. MATERIALS AND METHODS: Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, cell viability by CCK8, and apoptosis and cell death by flow cytometry in cultured prostate stromal cells (WPMY-1). Contractions of human prostate tissues from radical prostatectomy were induced by methoxamine, noradrenaline, phenylephrine, endothelin-1, U46619, or electric field stimulation (EFS) in an organ bath. KEY FINDINGS: Proliferation of WPMY-1 cells was significantly reduced by lenalidomide (5-200 µM) and pomalidomide (2.5-5 µM). In parallel, organization of actin filaments collapsed after treatment with lenalidomide and pomalidomide. Lenalidomide and pomalidomide inhibited both adrenergic contractions and non-adrenergic contractions as well as neurogenic contractions induced by EFS. Neither reduction in viability, nor increase in cell death or apoptosis was observed in WPMY-1 cells. SIGNIFICANCE: Thalidomide-derivatives impair growth of human prostate stromal cells, without showing a decrease in cell viability and, in parallel, inhibit adrenergic, neurogenic, and non-adrenergic contractions by breakdown of the actin cytoskeleton. Urodynamic effects in vivo appear possible.


Assuntos
Lenalidomida/farmacologia , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Talidomida/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular Transformada , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Próstata/citologia , Próstata/fisiologia , Talidomida/farmacologia
10.
J Med Chem ; 64(11): 7296-7311, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34042448

RESUMO

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN binders in the pursuit of targeting undruggable oncoproteins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Fatores de Terminação de Peptídeos/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Administração Oral , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Meia-Vida , Humanos , Fator de Transcrição Ikaros/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Estudos Retrospectivos , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Talidomida/metabolismo , Talidomida/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
11.
Bioorg Chem ; 111: 104901, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33878647

RESUMO

Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A-1F, in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B, connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC50 value of 0.23 ~ 0.39 µM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Talidomida/farmacologia , Triterpenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Proteólise/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Relação Estrutura-Atividade , Talidomida/química , Triterpenos/química
12.
Molecules ; 26(9)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926033

RESUMO

A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.


Assuntos
Antagonistas de Androgênios/química , Anilidas/química , Nitrilas/química , Receptores Androgênicos/química , Talidomida/química , Compostos de Tosil/química , Antagonistas de Androgênios/síntese química , Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Sítios de Ligação , Linhagem Celular , Técnicas de Química Sintética , Humanos , Modelos Biológicos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Nitrilas/farmacologia , Ligação Proteica , Proteólise/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Relação Estrutura-Atividade , Talidomida/farmacologia , Compostos de Tosil/farmacologia
13.
Eur J Med Chem ; 218: 113328, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33773286

RESUMO

Targeted therapy of treating patients with specific tyrosine kinase inhibitors (TKIs) is currently the standard care for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. However, the inevitably developed drug resistance in patients to EGFR TKIs is the biggest obstacle for cancer targeted therapy. About 60% of drug resistance to the 1st generation of EGFR TKIs was resulted from an acquired T790M mutation in the kinase domain of EGFR protein. Proteolysis targeting chimera (PROTAC) is a lately-developed technology to target point of interest proteins for degradation. Because EGFR-mutant lung cancers are highly dependent on EGFR proteins, designing specific PROTAC molecules to degrade EGFR proteins from cancer cells provides a very promising strategy to treat such patients and eradicate drug resistance. Currently, there is no cereblon (CRBN)-based PROTAC reported able to degrade T790M-containing EGFR resistant proteins. In this study, we synthesized two novel CRBN-based EGFR PROTACs, SIAIS125 and SIAIS126, based on EGFR inhibitor canertinib and cereblon ligand pomalidomide. These two degraders displayed potent and selective antitumor activities in EGFR TKI resistant lung cancer cells. Firstly, they could selectively degrade EGFRL858R+T790M resistant proteins in H1975 cells at the concentration of 30-50 nM, and EGFREx19del proteins in PC9 cells. But they did not degrade EGFREx19del+T790M mutant proteins in PC9Brca1 cells or wild type EGFR in A549 lung cancer cells. They could also selectively inhibit the growth of EGFR mutant lung cancer cells but not that of normal cells or A549 cells. Secondly, the degradation of EGFRL858R+T790M proteins was long lasting up to 72 h. Thirdly, these degraders displayed better inhibition of EGFR phosphorylation in H1975 cells and PC9Brca1 cells comparing to canertinib. Finally, these degraders could also induce significant apoptosis and cell cycles arrest in H1975 cells. Pre-incubation with canertinib, pomalidomide or ubiquitination inhibitor MLN4924 totally blocked EGFR degradation by PROTACs. Mechanistic studies showed that PROTAC could induce autophagy in lung cancer cells. PROTAC-induced EGFR degradation acted through both ubiquitin/proteosome system and ubiquitin/autophagy/lysosome system. Elevating autophagy activities enhanced EGFR degradation and cell apoptosis induced by PROTACs. Our research not only offered a novel PROTAC tool to target EGFR TKI drug resistance in lung cancer, but also firstly demonstrated that the involvement of autophagy/lysosome system in PROTAC- mediated target protein degradation.


Assuntos
Autofagia/efeitos dos fármacos , Morfolinas/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Talidomida/análogos & derivados , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Lisossomos/efeitos dos fármacos , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Mutação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Talidomida/síntese química , Talidomida/química , Talidomida/farmacologia
14.
Eur J Med Chem ; 218: 113341, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33780898

RESUMO

SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Talidomida/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Talidomida/síntese química , Talidomida/química , Células Tumorais Cultivadas
15.
Strahlenther Onkol ; 197(6): 537-546, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33688971

RESUMO

PURPOSE: In a previous study we have shown in a mouse model that administration of nuclear factor-kappa B (NF-κB) inhibitor thalidomide has promising therapeutic effects on early radiation cystitis (ERC) and late radiation sequelae (LRS) of the urinary bladder. The aim of this study was to evaluate in the same mice the effect of thalidomide on adherens junction (AJ) proteins in ERC and LRS. METHODS: Urothelial expressions of E­cadherin and ß­catenin were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) bladder specimens over 360 days post single-dose irradiation on day 0. First, the effect of irradiation on AJ expression and then effects of thalidomide on irradiation-induced AJ alterations were assessed using three different treatment times. RESULTS: Irradiation provoked a biphasic upregulation of E­cadherin and ß­catenin in the early phase. After a mild decrease of E­cadherin and a pronounced decrease of ß­catenin at the end of the early phase, both increased again in the late phase. Early administration of thalidomide (day 1-15) resulted in a steeper rise in the first days, an extended and increased expression at the end of the early phase and a higher expression of ß­catenin alone at the beginning of the late phase. CONCLUSION: Upregulation of AJ proteins is an attempt to compensate irradiation-induced impairment of urothelial barrier function. Early administration of thalidomide improves these compensatory mechanisms by inhibiting NF-κB signaling and its interfering effects.


Assuntos
Caderinas/biossíntese , Regulação da Expressão Gênica/efeitos da radiação , NF-kappa B/antagonistas & inibidores , Lesões Experimentais por Radiação/metabolismo , Talidomida/farmacologia , Bexiga Urinária/efeitos da radiação , beta Catenina/biossíntese , Junções Aderentes/efeitos da radiação , Animais , Caderinas/genética , Cistite/etiologia , Cistite/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C3H , Lesões Experimentais por Radiação/etiologia , Fatores de Tempo , Bexiga Urinária/metabolismo , Urotélio/metabolismo , Urotélio/efeitos da radiação , beta Catenina/genética
16.
Bioorg Chem ; 110: 104788, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33706076

RESUMO

Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.


Assuntos
Inibidores Enzimáticos/farmacologia , Piperidinas/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Pirimidinas/farmacologia , Talidomida/análogos & derivados , Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Pirimidinas/química , Relação Estrutura-Atividade , Talidomida/química , Talidomida/farmacologia
17.
Biochem Biophys Res Commun ; 549: 150-156, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33676183

RESUMO

Molecular glue degraders that hijack cellular E3 ubiquitin ligases to target disease-driven proteins for proteosome-dependent degradation are emerging as a promising treatment. Immunomodulatory drugs are classical molecular glue that bind to cereblon (CRBN) to repurpose the function of the CRL4(CRBN) E3 ubiquitin ligase and developed to treat various hematological malignancies. Recently, a novel cereblon modulator CC-885 was developed to elicit broad antitumor activity. Although the degradation of GSPT1 is essential for the broad in vitro antitumor activity of CC-885, it is unclear whether other neosubstrates also contribute to the pharmacological effects of CC-885, especially in multiple myeloma (MM). Here, we show that CC-885 treatment caused growth retardant of MM cells via impairment of cell cycle progression and cell death both in vitro and in vivo. Mechanically, CC-885 selectively induced the ubiquitination and degradation of CDK4 in MM cells in a CRBN-dependent manner. CC-885-mediated CDK4 destruction decreased the phosphorylation of the tumor suppressor retinoblastoma (RB) and prevented the expression of E2F downstream genes. Importantly, genetic ablation or pharmacological inhibition of CDK4 enhances CC-885-induced cytotoxicity in MM cells, suggesting CDK4 destruction contributed to the cytotoxicity of CC-885 in MM cells.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Mieloma Múltiplo/metabolismo , Compostos de Fenilureia/farmacologia , Proteólise , Talidomida/análogos & derivados , Ubiquitinação , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mieloma Múltiplo/patologia , Compostos de Fenilureia/química , Proteólise/efeitos dos fármacos , Especificidade por Substrato/efeitos dos fármacos , Talidomida/química , Talidomida/farmacologia , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J BUON ; 26(1): 2608-2615, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33721435

RESUMO

PURPOSE: To explore the efficacy and safety of 125 I radioactive seed implantation combined with intermittent hormonal therapy (IHT) in the clinical treatment of moderate- and high-risk non-metastatic prostate cancer. METHODS: A total of 136 patients were divided into the observation group (n=68) and the control group (n=68). In the observation group, 125I radioactive seed implantation was performed, bicalutamide capsules were taken orally immediately after operation, and leuprorelin was injected from 1 week after operation. In the control group, IHT alone was administered. The level of serum prostate specific antigen (PSA), maximum urine flow rate (Q max ) and international prostate symptom scale (IPSS) score were compared between the two groups before and after treatment. Moreover, the overall survival (OS), tumor-specific survival (TSS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) of patients were recorded. RESULTS: There were no statistically significant differences in the PSA level, Q max and IPSS score between the two groups before treatment (p>0.05). At 6, 12 and 24 months after treatment, the level of PSA in the observation group was significantly lower than in the control group (p=0.005, p<0.001, p<0.001). At 24 months after treatment, Q max in the observation group was significantly higher than in the control group (p=0.025). At 12 and 24 months after treatment, the IPSS score in the observation group was significantly lower than that in the control group (p=0.013, p=0.002). During the follow-up period, the intermission time of hormonal therapy and PFS time in the observation group were obviously longer than those in control group (p<0.001). In the two groups, OS was 97.1% and 94.1%, TSS was 95.6% and 92.6%, DMFS was 82.4% and 66.2%, and PFS was 72.1% and 51.5%, respectively. It can be seen that OS and TSS had no statistically significant differences between the two groups (p=0.405, p=0.496), while DMFS and PFS in the observation group were remarkably superior to those in the control group (p=0.037, p=0.022). CONCLUSIONS: 125 I seed implantation combined with IHT is safe and effective in the clinical treatment of patients with moderate- and high-risk non-metastatic prostate cancer. Compared with the IHT alone, the combination therapy can significantly prolong the intermission time of hormonal therapy and effectively control the progression of disease.


Assuntos
Terapia Combinada/métodos , Glioma/tratamento farmacológico , Glioma/radioterapia , Radioisótopos do Iodo/uso terapêutico , Radioterapia Conformacional/métodos , Temozolomida/uso terapêutico , Talidomida/uso terapêutico , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Temozolomida/farmacologia , Talidomida/farmacologia , Resultado do Tratamento
19.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33619107

RESUMO

Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.


Assuntos
Proteínas de Ciclo Celular/genética , Citomegalovirus/imunologia , DNA Viral/genética , Epigênese Genética , Histona Desacetilases/genética , Fator B de Elongação Transcricional Positiva/genética , Fatores de Transcrição/genética , Azepinas/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Benzodiazepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/imunologia , Ciclina T/genética , Ciclina T/imunologia , Quinase 9 Dependente de Ciclina/genética , Quinase 9 Dependente de Ciclina/imunologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Replicação do DNA/efeitos dos fármacos , DNA Viral/antagonistas & inibidores , DNA Viral/imunologia , Genes Precoces , Genes Reporter , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/imunologia , Interações Hospedeiro-Patógeno , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Modelos Biológicos , Fator B de Elongação Transcricional Positiva/imunologia , Cultura Primária de Células , Regiões Promotoras Genéticas , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/virologia , Células THP-1 , Talidomida/análogos & derivados , Talidomida/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/imunologia , Transcrição Genética , Ativação Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos
20.
Br J Clin Pharmacol ; 87(10): 3835-3850, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33609410

RESUMO

AIMS: The SARS-coV-2 pandemic continues to cause an unprecedented global destabilization requiring urgent attention towards drug and vaccine development. Thalidomide, a drug with known anti-inflammatory and immunomodulatory effects has been indicated to be effective in treating a SARS-coV-2 pneumonia patient. Here, we study the possible mechanisms through which thalidomide might affect coronavirus disease-19 (COVID-19). METHODS: The present study explores the possibility of repurposing thalidomide for the treatment of SARS-coV-2 pneumonia by reanalysing transcriptomes of SARS-coV-2 infected tissues with thalidomide and lenalidomide induced transcriptomic changes in transformed lung and haematopoietic models as procured from databases, and further comparing them with the transcriptome of primary endothelial cells. RESULTS: Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signalling, NOD-like receptor signalling, Toll-like receptor signalling, leucocyte differentiation and innate immunity, the processes that are aberrantly regulated in severe COVID-19 patients. CONCLUSION: The present study indicates thalidomide analogues as a better fit for treating severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , Reposicionamento de Medicamentos , Células Endoteliais , Humanos , Talidomida/farmacologia
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