Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
1.
Blood Adv ; 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39008716

RESUMO

Central nervous system (CNS) involvement remains a clinical hurdle in treating childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The disease mechanisms of CNS leukemia are primarily investigated using 2D cell culture and mouse models. Given the variations in cellular identity and architecture between the human and murine CNS, it becomes imperative to seek complementary models to study CNS leukemia. Here, we present a first-of-its-kind 3D co-culture model combining human brain organoids and BCP-ALL-cells. We noticed significantly higher engraftment of BCP-ALL cell lines and patient-derived xenograft (PDX) cells in cerebral organoids as compared to non-ALL-cells. To validate translatability between organoid co-culture and in vivo murine models, we confirmed that targeting CNS leukemia relevant pathways like CD79a/Igα or CXCR4-SDF1 reduced the invasion of BCP-ALL-cells into organoids. RNA sequencing and functional validations of organoid-invading leukemia cells compared to the non-invaded fraction revealed significant upregulation of AP-1 transcription factor-complex members in organoid-invading cells. Moreover, we detected a significant enrichment of AP-1 pathway genes in ALL-PDX-cells recovered from the CNS compared to spleen blasts of mice transplanted with TCF3::PBX1+ PDX-cells, substantiating the role of AP-1 signaling in CNS disease. Accordingly, we found significantly higher levels of the AP-1-gene JUN in patients initially diagnosed as CNS-positive compared to CNS-negative cases as well as CNS-relapse vs non-CNS-relapse cases in a cohort of 100 BCP-ALL-patients. Our results suggest CNS-organoids as a novel model to investigate CNS-involvement and identify the AP-1 pathway as a critical driver of CNS-disease in BCP-ALL.

2.
Cell Death Discov ; 10(1): 279, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862521

RESUMO

A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.

3.
Eur J Med Chem ; 272: 116447, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38714044

RESUMO

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues of the preferential HDAC6 inhibitor HPOB in only two steps via an Ugi four-component reaction as the key step. Biochemical HDAC inhibition and cell viability assays led to the identification of 1g (highest antileukemic activity) and 2b (highest HDAC6 inhibition) as hit compounds. In subsequent combination screens, both 1g and especially 2b showed synergy with DNA methyltransferase inhibitor decitabine in acute myeloid leukemia (AML). Our findings highlight the potential of combining HDAC6 inhibitors with DNA methyltransferase inhibitors as a strategy to improve AML treatment outcomes.


Assuntos
Antineoplásicos , Decitabina , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Leucemia Mieloide Aguda , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Decitabina/farmacologia , Decitabina/química , Relação Estrutura-Atividade , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Aminopiridinas , Benzamidas
5.
Cell Death Discov ; 10(1): 125, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461295

RESUMO

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2-3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

7.
Cell Death Dis ; 14(12): 799, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057328

RESUMO

HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance acquisition via heat shock response (HSR) induction. Understanding the roles of abundantly expressed cytosolic HSP90 isoforms (α and ß) in sustaining malignant cells' growth and the mechanisms of resistance to HSP90i is crucial for exploiting their clinical potential. Utilizing multi-omics approaches, we identified that ablation of the HSP90ß isoform induces the overexpression of HSP90α and extracellular-secreted HSP90α (eHSP90α). Notably, we found that the absence of HSP90α causes downregulation of PTPRC (or CD45) expression and restricts in vivo growth of BCR-ABL1+ leukemia cells. Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.


Assuntos
Antineoplásicos , Proteínas de Choque Térmico HSP90 , Leucemia , Neoplasias , Humanos , Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Leucemia/tratamento farmacológico , Leucemia/genética , Mutação , Resistencia a Medicamentos Antineoplásicos
9.
Biochem Pharmacol ; 217: 115809, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37717691

RESUMO

Although a great cure rate has been achieved for pediatric BCP-ALL, approximately 15% of patients do not respond to conventional chemotherapy and experience disease relapse. A major effort to improve the cure rates by treatment intensification would result in an undesirable increase in treatment-related toxicity and mortality, raising the need to identify novel therapeutic approaches. High-throughput (HTP) drug screening enables the profiling of patients' responses in vitro and allows the repurposing of compounds currently used for other diseases, which can be immediately available for clinical application. The aim of this study was to apply HTP drug screening to identify potentially effective compounds for the treatment of pediatric BCP-ALL patients with poor prognosis, such as patients with Down Syndrome (DS) or carrying rearrangements involving PAX5 or KMT2A/MLL genes. Patient-derived Xenografts (PDX) samples from 34 BCP-ALL patients (9 DS CRLF2r, 15 PAX5r, 10 MLLr), 7 human BCP-ALL cell lines and 14 hematopoietic healthy donor samples were screened on a semi-automated HTP drug screening platform using a 174 compound library (FDA/EMA-approved or in preclinical studies). We identified 9 compounds active against BCP-ALL (ABT-199/venetoclax, AUY922/luminespib, dexamethasone, EC144, JQ1, NVP-HSP990, paclitaxel, PF-04929113 and vincristine), but sparing normal cells. Ex vivo validations confirmed that the BCL2 inhibitor venetoclax exerts an anti-leukemic effect against all three ALL subgroups at nanomolar concentrations. Overall, this study points out the benefit of HTP screening application for drug repurposing to allow the identification of effective and clinically translatable therapeutic agents for difficult-to-treat childhood BCP-ALL subgroups.


Assuntos
Reposicionamento de Medicamentos , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Ensaios de Triagem em Larga Escala , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico
10.
Mol Cancer ; 22(1): 136, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37582744

RESUMO

BACKGROUND: New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. To uncover novel potentiators of T cell anti-tumor immunity, we carried out an ex vivo pharmacological screen and identified 5-Nonyloxytryptamine (5-NL), a serotonin agonist, as increasing the ability of T cells to target tumor cells. METHODS: The pharmacological screen utilized lymphocytic choriomeningitis virus (LCMV)-primed splenic T cells and melanoma B16.F10 cells expressing the LCMV gp33 CTL epitope. In vivo tumor growth in C57BL/6 J and NSG mice, in vivo antibody depletion, flow cytometry, immunoblot, CRISPR/Cas9 knockout, histological and RNA-Seq analyses were used to decipher 5-NL's immunomodulatory effects in vitro and in vivo. RESULTS: 5-NL delayed tumor growth in vivo and the phenotype was dependent on the hosts' immune system, specifically CD8+ T cells. 5-NL's pro-immune effects were not directly consequential to T cells. Rather, 5-NL upregulated antigen presenting machinery in melanoma and other tumor cells in vitro and in vivo without increasing PD-L1 expression. Mechanistic studies indicated that 5-NL's induced MHC-I expression was inhibited by pharmacologically preventing cAMP Response Element-Binding Protein (CREB) phosphorylation. Importantly, 5-NL combined with anti-PD1 therapy showed significant improvement when compared to single anti-PD-1 treatment. CONCLUSIONS: This study demonstrates novel therapeutic opportunities for augmenting immune responses in poorly immunogenic tumors.


Assuntos
Linfócitos T CD8-Positivos , Melanoma , Camundongos , Animais , Regulação para Cima , Camundongos Endogâmicos C57BL , Vírus da Coriomeningite Linfocítica/genética , Melanoma/tratamento farmacológico
11.
Front Chem ; 11: 1219883, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37448856

RESUMO

Despite the early clinical promise, adverse events such as acquired resistance and dose-limiting toxicities have barred the widespread use of HSP90 inhibitors as anticancer drugs. A new approach involving proteolysis-targeting chimeras (PROTACs) to degrade the protein instead of inhibiting it may overcome these problems. In this work, we describe the design, synthesis, and evaluation of cereblon-recruiting geldanamycin-based HSP90 degraders based on the PROTAC technology. Our best degrader, 3a, effectively decreased HSP90α and HSP90ß levels in cells utilizing the ubiquitin-proteasome pathway.

12.
Hemasphere ; 7(6): e892, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37304931

RESUMO

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.

13.
J Med Chem ; 65(24): 16860-16878, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36473103

RESUMO

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of histone deacetylase 6 (HDAC6). Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin-proteasome pathway, with DC50 values of 3.5 and 19.4 nM, respectively. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.


Assuntos
Antineoplásicos , Desacetilase 6 de Histona , Antineoplásicos/farmacologia , Quimera de Direcionamento de Proteólise , Técnicas de Síntese em Fase Sólida , Proliferação de Células , Proteólise , Ubiquitina-Proteína Ligases/metabolismo
14.
J Med Chem ; 65(22): 15457-15472, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36351184

RESUMO

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Peptoides , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/química , Desacetilase 6 de Histona , Peptoides/farmacologia , Peptoides/química , Decitabina , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Leucemia Mieloide Aguda/tratamento farmacológico , Linhagem Celular Tumoral , Histona Desacetilase 1 , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Ácidos Hidroxâmicos/química
15.
Cell Death Dis ; 13(11): 938, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36347842

RESUMO

Inhibition of the mitochondrial metabolism offers a promising therapeutic approach for the treatment of cancer. Here, we identify the mycotoxin viriditoxin (VDT), derived from the endophytic fungus Cladosporium cladosporioides, as an interesting candidate for leukemia and lymphoma treatment. VDT displayed a high cytotoxic potential and rapid kinetics of caspase activation in Jurkat leukemia and Ramos lymphoma cells in contrast to solid tumor cells that were affected to a much lesser extent. Most remarkably, human hematopoietic stem and progenitor cells and peripheral blood mononuclear cells derived from healthy donors were profoundly resilient to VDT-induced cytotoxicity. Likewise, the colony-forming capacity was affected only at very high concentrations, which provides a therapeutic window for cancer treatment. Intriguingly, VDT could directly activate the mitochondrial apoptosis pathway in leukemia cells in the presence of antiapoptotic Bcl-2 proteins. The mitochondrial toxicity of VDT was further confirmed by inhibition of mitochondrial respiration, breakdown of the mitochondrial membrane potential (ΔΨm), the release of mitochondrial cytochrome c, generation of reactive oxygen species (ROS), processing of the dynamin-like GTPase OPA1 and subsequent fission of mitochondria. Thus, VDT-mediated targeting of mitochondrial oxidative phosphorylation (OXPHOS) might represent a promising therapeutic approach for the treatment of leukemia and lymphoma without affecting hematopoietic stem and progenitor cells.


Assuntos
Leucemia , Linfoma , Micotoxinas , Humanos , Micotoxinas/metabolismo , Leucócitos Mononucleares/metabolismo , Apoptose , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Linfoma/tratamento farmacológico , Linfoma/metabolismo , Potencial da Membrana Mitocondrial
16.
EBioMedicine ; 83: 104224, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35985167

RESUMO

BACKGROUND: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. METHODS: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. FINDINGS: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. INTERPRETATION: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. FUNDING: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazione Cariparo.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Subunidade alfa 2 de Fator de Ligação ao Core , Dasatinibe , Dexametasona , Humanos , Indóis , Recidiva Local de Neoplasia , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
17.
ACS Cent Sci ; 8(5): 636-655, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35647282

RESUMO

Heat shock proteins 90 (Hsp90) are promising therapeutic targets due to their involvement in stabilizing several aberrantly expressed oncoproteins. In cancerous cells, Hsp90 expression is elevated, thereby exerting antiapoptotic effects, which is essential for the malignant transformation and tumor progression. Most of the Hsp90 inhibitors (Hsp90i) under investigation target the ATP binding site in the N-terminal domain of Hsp90. However, adverse effects, including induction of the prosurvival resistance mechanism (heat shock response or HSR) and associated dose-limiting toxicity, have so far precluded their clinical approval. In contrast, modulators that interfere with the C-terminal domain (CTD) of Hsp90 do not inflict HSR. Since the CTD dimerization of Hsp90 is essential for its chaperone activity, interfering with the dimerization process by small-molecule protein-protein interaction inhibitors is a promising strategy for anticancer drug research. We have developed a first-in-class small-molecule inhibitor (5b) targeting the Hsp90 CTD dimerization interface, based on a tripyrimidonamide scaffold through structure-based molecular design, chemical synthesis, binding mode model prediction, assessment of the biochemical affinity, and efficacy against therapy-resistant leukemia cells. 5b reduces xenotransplantation of leukemia cells in zebrafish models and induces apoptosis in BCR-ABL1+ (T315I) tyrosine kinase inhibitor-resistant leukemia cells, without inducing HSR.

18.
Int J Mol Sci ; 23(9)2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35563565

RESUMO

Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.


Assuntos
Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Linfoma , Leucemia-Linfoma Linfoblástico de Células Precursoras , Apoptose , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Criança , Proteínas de Ligação a DNA/genética , Síndrome de Cornélia de Lange/genética , Pontos de Checagem da Fase G2 do Ciclo Celular , Células Germinativas/metabolismo , Humanos , Linfoma/genética , Mutação , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
19.
Front Immunol ; 13: 856230, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35464417

RESUMO

Beauvericin (BEA), a mycotoxin of the enniatin family produced by various toxigenic fungi, has been attributed multiple biological activities such as anti-cancer, anti-inflammatory, and anti-microbial functions. However, effects of BEA on dendritic cells remain unknown so far. Here, we identified effects of BEA on murine granulocyte-macrophage colony-stimulating factor (GM-CSF)-cultured bone marrow derived dendritic cells (BMDCs) and the underlying molecular mechanisms. BEA potently activates BMDCs as signified by elevated IL-12 and CD86 expression. Multiplex immunoassays performed on myeloid differentiation primary response 88 (MyD88) and toll/interleukin-1 receptor (TIR) domain containing adaptor inducing interferon beta (TRIF) single or double deficient BMDCs indicate that BEA induces inflammatory cytokine and chemokine production in a MyD88/TRIF dependent manner. Furthermore, we found that BEA was not able to induce IL-12 or IFNß production in Toll-like receptor 4 (Tlr4)-deficient BMDCs, whereas induction of these cytokines was not compromised in Tlr3/7/9 deficient BMDCs. This suggests that TLR4 might be the functional target of BEA on BMDCs. Consistently, in luciferase reporter assays BEA stimulation significantly promotes NF-κB activation in mTLR4/CD14/MD2 overexpressing but not control HEK-293 cells. RNA-sequencing analyses further confirmed that BEA induces transcriptional changes associated with the TLR4 signaling pathway. Together, these results identify TLR4 as a cellular BEA sensor and define BEA as a potent activator of BMDCs, implying that this compound can be exploited as a promising candidate structure for vaccine adjuvants or cancer immunotherapies.


Assuntos
Micotoxinas , Receptor 4 Toll-Like , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Citocinas/metabolismo , Células Dendríticas , Depsipeptídeos , Células HEK293 , Humanos , Interleucina-12/metabolismo , Camundongos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
20.
Pharmaceuticals (Basel) ; 15(3)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35337131

RESUMO

Artemisinin-based combination therapies (ACTs) are the gold standard for the treatment of malaria, but the efficacy is threatened by the development of parasite resistance. Histone deacetylase inhibitors (HDACis) are an emerging new class of potential antiplasmodial drugs. In this work, we present the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin-HDACi hybrid molecules. The screening of the hybrid molecules for their activity against selected human HDAC isoforms, asexual blood stage P. falciparum parasites, and a panel of leukemia cell lines delivered important structure-activity relationships. All synthesized compounds demonstrated potent activity against the 3D7 and Dd2 line of P. falciparum with IC50 values in the single-digit nanomolar range. Furthermore, the hybrid (α)-7c displayed improved activity against artemisinin-resistant parasites compared to dihydroartemisinin. The screening of the compounds against five cell lines from different leukemia entities revealed that all hydroxamate-based hybrids (7a-e) and the ortho-aminoanilide 8 exceeded the antiproliferative activity of dihydroartemisinin in four out of five cell lines. Taken together, this series of hybrid molecules represents an excellent starting point toward the development of antimalarial and antileukemia drug leads.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...