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1.
Drug Discov Today ; 2022 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-35760282

RESUMO

Drug resistance to chemotherapy and molecularly targeted therapies is a current challenge in cancer treatments. The underlying mechanisms of resistance to cytotoxic chemotherapeutics and to drugs that target a specific molecule are not understood completely. In recent years, emerging evidence has frequently suggested that the dysregulation of deubiquitinating enzymes (DUBs) plays important roles in the development of drug resistance. We focus on the molecular mechanisms through which DUBs enable cancer cells to escape cell death and survive when exposed to a variety of anti-cancer drugs. Furthermore, this review summarizes the potential application of DUB inhibitors in combination therapies to overcome drug resistance.

2.
Biochem Pharmacol ; 202: 115142, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35700755

RESUMO

Acetaminophen (APAP) hepatotoxicity is an important cause of acute liver failure, resulting in massive deaths in many developed countries. Currently, the metabolic process of APAP in the body has been well studied. However, the underlying mechanism of APAP-induced liver injury remains elusive. Increasing clinical and experimental evidences indicate that the innate immune responses are involved in the pathogenesis of APAP-induced acute liver injury (AILI), in which immune cells have dual roles of inducing inflammation to exacerbate hepatotoxicity and removing dead cells and debris to help liver regeneration. In this review, we summarize the latest findings of innate immune cells involved in AILI, particularly emphasizing the activation of innate immune cells and their different roles during the injury and repair phases. Moreover, current available treatments are discussed according to the different roles of innate immune cells in the development of AILI. This review aims to update the knowledge about innate immune responses in the pathogenesis of AILI, and provide potential therapeutic interventions for AILI.

3.
Front Pharmacol ; 13: 897747, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721177

RESUMO

Given the limitations of the existing antibody-based therapies, including immune-related adverse events, poor response rates, and intravenous route of dosing, small molecules inhibitors targeting PD-L1 are highly desirable. By cell-based screening, we found that tyrosine kinase inhibitor Bafetinib dramatically suppresses PD-L1 protein expression in a dose-dependent manner. In parallel, cell membrane PD-L1 is also reduced by Bafetinib. We confirm that Bafetinib doesn't affect the protein half-life of PD-L1 but significantly inhibits the transcription of PD-L1. Among the transcription factors that regulate PD-L1 expression, c-Myc is downregulated by Bafetinib. Bafetinib caused PD-L1 inhibition is abolished when c-Myc is knocked-down. Further, we identified that Bafetinib reduced c-Myc expression because of transcription inhibition. By using the CT26 tumor model, we further confirm that Bafetinib suppressed PD-L1 expression in vivo. In conclusion, our study shows that Bafetinib inhibits the transcription of PD-L1 through transcription factor c-Myc, suggesting that Bafetinib might be a small molecule drug targeting PD-L1.

4.
Hepatology ; 2022 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-35713976

RESUMO

BACKGROUND & AIMS: Succinate dehydrogenase enzyme (SDH) is frequently diminished in Hepatocellular carcinoma (HCC) patient samples, and SDH reduction is associated with elevated succinate level and poor prognosis in HCC patients. But the underlying mechanisms about how impaired SDH activity promotes HCC remain unclear. APPROACH & RESULTS: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples. Subsequent RNA sequencing, hematoxylin & eosin (H&E) staining and immunohistochemistry (IHC) analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. YAP/TAZ stability was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation which facilitated the deNEDDylation of cullin1, therefore disrupted the E3 ubiquitin ligase SCFß-TrCP complex, consequently led to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. CONCLUSIONS: Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus addicts SDH-deficient HCC cells to YAP/TAZ pathway and renders these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in HCC patients displaying reduced SDHA/B or elevated succinate levels.

5.
Bioorg Chem ; 125: 105820, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35569191

RESUMO

Immune checkpoint blockade (ICB) by targeting programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway is a promising strategy for tumor immunotherapy. Developing small-molecules inducing PD-L1 protein degradation has been proven as an alternative and useful approach for targeting the immunotherapy pathway. Our previous study showed that Lercanidipine could down-regulate the expression of PD-L1 protein, but its calcium influx antagonistic activity hampers further development. For attenuating the unexpected calcium channel blockade effect, a series of compounds were synthesized and evaluated through structure-activity relationship (SAR) exploration. Amongst, compound F4 exhibited a loss of calcium antagonistic activity, while the PD-L1 degradation activity can still retain. Further studies indicated that F4 degraded PD-L1 dose- and time-dependently, and may function through a lysosomal-dependent manner. Furthermore, compound F4 showed a good bioavailability value of 24.9% in mice. Moreover, the F4-induced PD-L1 degradation strengthened the T cell-mediated killing of tumor cells. Our findings show the discovery of a new PD-L1 degrader, providing a potential strategy for immunotherapy.


Assuntos
Antígeno B7-H1 , Di-Hidropiridinas , Animais , Antígeno B7-H1/metabolismo , Cálcio , Di-Hidropiridinas/farmacologia , Imunoterapia , Camundongos , Linfócitos T
6.
Eur J Pharmacol ; 926: 175035, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35605658

RESUMO

As a key regulator involved in tumor development and progression, DJ-1 has been proposed as a potential therapeutic target against cancer. Also, the development of DJ-1 inhibitors holds great interests in cancer treatment. In the current study, by utilizing a small molecule covalent compounds library screening, we found that disulfiram (DSF), an FDA-approved chronic alcoholism drug, is a potent DJ-1 inhibitor. Glyoxalase assay and microscale thermophoresis analysis suggested that DSF exhibits strong inhibitory activity and high affinity to DJ-1 protein. Additionally, DSF similarly inhibited the methylglyoxal detoxification function of DJ-1 protein at the intracellular level. Notably, we discovered that DSF could significantly enhance N-(4-hydroxyphenyl) retinamide-based proliferation inhibition and apoptosis induction in different types of cancer cell lines, but not in normal tissue lines. Thus, our data suggest DSF functions as a potential inhibitor targeting DJ-1, which may provide a potential synergistic treatment option for cancer therapy.


Assuntos
Antineoplásicos , Dissulfiram , Neoplasias , Proteína Desglicase DJ-1 , Dissuasores de Álcool/farmacologia , Dissuasores de Álcool/uso terapêutico , Alcoolismo/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doença Crônica , Cobre , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteína Desglicase DJ-1/antagonistas & inibidores , Proteína Desglicase DJ-1/genética
7.
Eur J Pharmacol ; 927: 175071, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35636522

RESUMO

Epigenetic dysregulation plays a crucial role in the development and progression of ovarian cancer. Since the first experiment conducted on resistant ovarian cancer cells using demethylating drugs, multiple clinical trials have revealed that epigenetic targeted drugs combined with chemotherapy, molecular-targeted drugs, or even immunotherapy could enhance tumor sensitivity and reverse acquired resistances. Here, we summarized the combination strategies of epigenetic targeted drugs with other treatment strategies of ovarian cancer and discussed the principles of combination therapy. Finally, we enumerated several reasonable clinical trial designs as well as future drug development strategies, which may provide promising ideas for the application of epigenetic drugs to ovarian cancer.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia
8.
Biochem Pharmacol ; 201: 115105, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35617997

RESUMO

The application of lapatinib, a widely used dual inhibitor of human epidermal growth factor receptor 1 (EGFR/ERBB1) and 2 (HER2/ERBB2), has been seriously limited due to cutaneous toxicity. However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to the lack of an effective strategy to improve clinical safety. Here, we found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and ultimately cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce an aberrant immune response and promote the release of inflammatory factors in vitro and in vivo. Mechanistically, downregulated expression of the DNA repair protein HMGB1 played a critical role in these toxic reaction processes. Overexpression of HMGB1 inhibited keratinocyte apoptosis and inflammatory reactions. Therefore, restoring HMGB1 expression might be an effective remedy against lapatinib-induced cutaneous toxicity. Finally, we found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent the toxicity of lapatinib in mice. Collectively, our study might bring new hope to clinicians and tumor patients and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.


Assuntos
Antineoplásicos , Proteína HMGB1 , Neoplasias , Animais , Antineoplásicos/toxicidade , Apoptose , Linhagem Celular Tumoral , Proteína HMGB1/genética , Humanos , Lapatinib/toxicidade , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/toxicidade , Receptor ErbB-2/metabolismo
9.
Acta Pharm Sin B ; 12(3): 1225-1239, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35530152

RESUMO

The dysregulation of transcription factors is widely associated with tumorigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the ß-catenin pathway. Mechanistically, WSB1 affected ß-catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor ß-TRCP recruitment, which inhibited the ubiquitination of ß-catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumor-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumorigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

11.
BMC Cancer ; 22(1): 425, 2022 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440025

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome. MATERIALS AND METHODS: The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia. RESULTS: Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC. CONCLUSIONS: Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia , Neoplasias Hepáticas/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas , Pirróis , Sorafenibe/farmacologia , Sorafenibe/uso terapêutico , Sulfonamidas
12.
Front Pharmacol ; 13: 841687, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35281921

RESUMO

CCR7, collaborated with its ligands CCL19 and CCL21, controls extensive migratory events in the immune system. CCR7-bearing dendritic cells can swarm into T-cell zones in lymph nodes, initiating the antigen presentation and T-cell response. Abnormal expression of CCR7 in dendritic cells will cause a series of inflammatory diseases due to the chaotic dendritic cell trafficking. In this review, we take an in-depth look at the structural-functional domains of CCR7 and CCR7-bearing dendritic cell trajectory to lymph nodes. Then, we summarize the regulatory network of CCR7, including transcriptional regulation, translational and posttranslational regulation, internalization, desensitization, and recycling. Furthermore, the potential strategies of targeting the CCR7 network to regulate dendritic cell migration and to deal with inflammatory diseases are integrated, which not only emphasizes the possibility of CCR7 to be a potential target of immunotherapy but also has an implication on the homing of dendritic cells to benefit inflammatory diseases.

13.
Biomed Pharmacother ; 149: 112869, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35358798

RESUMO

Organoids are in vitro simplified and miniature microcosms of internal organs, which have aroused great interest in tissue development, multiple disease models, clinical diagnosis, as well as high-throughput drug screening and personalized medicine and so on. The success of physiology-related organoid culture has greatly advanced the translational medicine research in the field of cancer treatment, which was once troubled by the inconsistency between two-dimensional (2D) cell culture and in vivo studies. Especially in recent years, the success rate of establish an organoid has been greatly improved, and the types of organoids have been gradually enriched. Moreover, the utilizing of some the cutting-edge technologies, including gene editing technology such as CRISPR-Cas9, the scope of application of organoid is broadened. In this review, we discuss the latest progress and applications of organoids, and also outline the potential challenges of organoids for future improvement.


Assuntos
Neoplasias , Organoides , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medicina de Precisão , Tecnologia
14.
Cell Death Differ ; 2022 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-35194189

RESUMO

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML/RARα, which destroys the architecture of PML nuclear bodies (NBs). PML NBs are critical to tumor suppression, and their disruption mediated by PML/RARα accelerates APL pathogenesis. However, the mechanisms of PML NB disruption remain elusive. Here, we reveal that the failure of NB assembly in APL results from neddylation-induced aberrant phase separation of PML/RARα. Mechanistically, PML/RARα is neddylated in the RARα moiety, and this neddylation enhances its DNA-binding ability and further impedes the phase separation of the PML moiety, consequently disrupting PML NB construction. Accordingly, deneddylation of PML/RARα restores its phase separation process to reconstruct functional NBs and activates RARα signaling, thereby suppressing PML/RARα-driven leukemogenesis. Pharmacological inhibition of neddylation by MLN4924 eradicates APL cells both in vitro and in vivo. Our work elucidates the neddylation-destroyed phase separation mechanism for PML/RARα-driven NB disruption and highlights targeting neddylation for APL eradication.

15.
J Med Chem ; 65(5): 3849-3865, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35191698

RESUMO

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable. Through the scaffold-hopping strategy, indazole was first described as the core structure of propeller-shaped PI3Kδ inhibitors. A total of 26 indazole derivatives were designed and prepared to identify a novel compound 9x with good isoform selectivity, PK profile, and potency. Compared to Idelalisib and Sorafenib, the pharmacodynamic (PD) studies showed that 9x exhibits superior efficacy in HCC cell lines and xenograft models, and the mechanistic study showed that 9x robustly suppresses the downstream AKT pathway to induce subsequent apoptotic cell death in HCC models. Therefore, this work provides a new structural design of PI3Kδ inhibitors for a novel and efficient therapeutic small molecule toward HCC.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Humanos , Indazóis/farmacologia , Indazóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
16.
Bioorg Chem ; 121: 105673, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35217375

RESUMO

Fibroblast growth factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo
17.
Acta Pharm Sin B ; 12(1): 18-32, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35127370

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrotic interstitial pneumonia with unknown causes. The incidence rate increases year by year and the prognosis is poor without cure. Recently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway can be considered as a master regulator for IPF. The contribution of the PI3K/AKT in fibrotic processes is increasingly prominent, with PI3K/AKT inhibitors currently under clinical evaluation in IPF. Therefore, PI3K/AKT represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. This review epitomizes the progress that is being made in understanding the complex interpretation of the cause of IPF, and demonstrates that PI3K/AKT can directly participate to the greatest extent in the formation of IPF or cooperate with other pathways to promote the development of fibrosis. We further summarize promising PI3K/AKT inhibitors with IPF treatment benefits, including inhibitors in clinical trials and pre-clinical studies and natural products, and discuss how these inhibitors mitigate fibrotic progression to explore possible potential agents, which will help to develop effective treatment strategies for IPF in the near future.

18.
Acta Pharmacol Sin ; 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-35022542

RESUMO

Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 µM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 µM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.

19.
Acta Pharmacol Sin ; 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042992

RESUMO

Cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) is a DNA sensor that detects and binds to cytosolic DNA to generate cyclic GMP-AMP (cGAMP). As a second messenger, cGAMP mainly activates the adapter protein STING, which induces the production of type I interferons (IFNs) and inflammatory cytokines. Mounting evidence shows that cGAS is extensively involved in the innate immune response, senescence, and tumor immunity, thereby exhibiting a tumor-suppressive function, most of which is mediated by the STING pathway. In contrast, cGAS can also act as an oncogenic factor, mostly by increasing genomic instability through inhibitory effects on DNA repair, suggesting its utility as an antitumor target. This article reviews the roles and the underlying mechanisms of cGAS in cancer, particularly focusing on its dual roles in carcinogenesis and tumor progression, which are probably attributable to its classical and nonclassical functions, as well as approaches targeting cGAS for cancer therapy.

20.
Eur J Med Chem ; 228: 114012, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34864331

RESUMO

Cyclin-dependent kinase 12 (CDK12) plays a crucial role in DNA-damage response gene transcription and has recently been validated as a promising target in cancer therapy. However, existing CDK12 inhibitors potently inhibit its closest isoform CDK13, which could cause potential toxicity. Therefore, the development of CDK12 inhibitors with isoform-selectivity against CDK13 continues to be a challenge. By taking advantage of the emerging PROteolysis-TArgeting Chimeras (PROTACs) approach, we have synthesized a potent PROTAC degrader PP-C8 based on the noncovalent dual inhibitors of CDK12/13 and demonstrated its specificity for CDK12 over CDK13. Notably, PP-C8 induces profound degradation of cyclin K simultaneously and downregulates the mRNA level of DNA-damage response genes. Global proteomics profiling revealed PP-C8 is highly selective toward CDK12-cyclin K complex. Importantly, PP-C8 demonstrates profound synergistic antiproliferative effects with PARP inhibitor in triple-negative breast cancer (TNBC). The potent and selective CDK12 PROTAC degrader developed in this study could potentially be used to treat CDK12-dependent cancers as combination therapy.


Assuntos
Proteína Quinase CDC2/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Ciclinas/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteína Quinase CDC2/metabolismo , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/metabolismo , Ciclinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade
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