RESUMO
Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases , Histona Desacetilases , Ácidos Hidroxâmicos , Fenotiazinas , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/síntese química , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Fenotiazinas/farmacologia , Fenotiazinas/química , Fenotiazinas/síntese química , Apoptose/efeitos dos fármacos , Modelos Moleculares , Linhagem Celular TumoralRESUMO
Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant+Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC50 = 0.012 µM and 0.035 µM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.
Assuntos
Caenorhabditis elegans , Inibidores de Histona Desacetilases , Indóis , Animais , Indóis/química , Indóis/farmacologia , Indóis/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Humanos , Caenorhabditis elegans/efeitos dos fármacos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/síntese química , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Relação Estrutura-Atividade , Doenças Neurodegenerativas/tratamento farmacológico , Animais Geneticamente Modificados , Drosophila , Doença de Parkinson/tratamento farmacológico , Modelos Animais de Doenças , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Doença de Alzheimer/tratamento farmacológicoRESUMO
Epigenetic therapies have emerged as a key paradigm for treating malignancies. In this study, a series of DNMT1/HDAC dual inhibitors were obtained by fusing the key pharmacophores from DNMT1 inhibitors (DNMT1i) and HDAC inhibitors (HDACi). Among them, compound (R)-23a demonstrated significant DNMT1 and HDAC inhibition both in vitro and in cells and largely phenocopied the synergistic effects of combined DNMT1i and HDACi in reactivating epigenetically silenced tumor suppressor genes (TSGs). This translated into a profound tumor growth inhibition (TGI = 98%) of (R)-23a in an MV-4-11 xenograft model, while displaying improved tolerability compared with single agent combination. Moreover, in a syngeneic MC38 mouse colorectal tumor model, (R)-23a outperformed the combinatory treatment in reshaping the tumor immune microenvironment and inducing tumor regression. Collectively, the novel DNMT1/HDAC dual inhibitor (R)-23a effectively reverses the cancer-specific epigenetic abnormalities and holds great potential for further development into cancer therapeutic agents.
Assuntos
Antineoplásicos , DNA (Citosina-5-)-Metiltransferase 1 , Inibidores de Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/síntese química , Animais , DNA (Citosina-5-)-Metiltransferase 1/antagonistas & inibidores , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Proliferação de Células/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , FemininoRESUMO
HDAC8 can mediate signals by using its enzymatic or nonenzymatic functions, which are expected to be critical for various types of cancer. Herein, we employed proteolysis targeting chimera (PROTAC) technology to target the enzymatic as well as the nonenzymatic functions of HDAC8. A potent and selective HDAC8 PROTAC Z16 (CZH-726) with low nanomolar DC50 values in various cell lines was identified. Interestingly, Z16 induced structural maintenance of chromosomes protein 3 (SMC3) hyperacetylation at low concentrations and histone hyperacetylation at high concentrations, which can be explained by HDAC8 degradation and off-target HDAC inhibition, respectively. Notably, Z16 potently inhibited proliferation of various cancer cell lines and the antiproliferative mechanisms proved to be cell-type-dependent, which, to a large extent, is due to off-target HDAC inhibition. In conclusion, we report a hydrazide-based HDAC8 PROTAC Z16, which can be used as a probe to investigate the biological functions of HDAC8.
Assuntos
Proliferação de Células , Inibidores de Histona Desacetilases , Histona Desacetilases , Hidrazinas , Proteólise , Proteínas Repressoras , Humanos , Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Proteólise/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Hidrazinas/farmacologia , Hidrazinas/química , Hidrazinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Quimera de Direcionamento de ProteóliseRESUMO
Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying HL-5s with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, HL-5s induces ferroptosis by augmenting LPO production. Mechanistically, HL-5s increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, HL-5s not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and HL-5s may serve as a promising candidate for future cancer treatment.
Assuntos
Antineoplásicos , Benzimidazóis , Ferroptose , Inibidores de Histona Desacetilases , Morte Celular Imunogênica , Ferroptose/efeitos dos fármacos , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Animais , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Benzimidazóis/farmacologia , Benzimidazóis/química , Morte Celular Imunogênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Descoberta de Drogas , Proliferação de Células/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Co-inhibition of histone deacetylase (HDAC) and cyclin-dependent kinase (CDK) synergizes to produce enhanced antitumor effects and potentially overcomes the drug resistance. In this work, we discovered a series of novel CDK9/HDACs dual inhibitors. Among them, compound 8e was identified to show potent CDK9 and HDAC1 inhibitory activities, with IC50 values at 88.4 and 168.9 nM, respectively, and exhibited antiproliferative capacities against hematological and solid tumor cells. Meanwhile, 8e showed high selectivity for CDK9 and HDAC1, remarkably induced MV-4-11 cell apoptosis and S cell cycle arrests. Furthermore, 8e possessed a significant antitumor potency with a T/C value of 29.98% in the MV-4-11 xenograft model. Interestingly, a potent FLT3/HDAC dual inhibitor 9e was also identified (FLT3/HDAC1/3 IC50 = 30.4/52.4/14.7 nM) and found to possess powerful apoptosis induction ability in MV-4-11 cell and potent antiproliferative capacities against FLT3 mutant-transformed BaF3 cells. Overall, our work provided valuable lead compounds for dual inhibitors with potent anticancer activity.
Assuntos
Aminopiridinas , Antineoplásicos , Inibidores de Histona Desacetilases , Pirimidinas , Humanos , Animais , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Aminopiridinas/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/química , Pirimidinas/farmacologia , Pirimidinas/química , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Relação Estrutura-Atividade , Camundongos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Quinase 9 Dependente de Ciclina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Descoberta de Drogas , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos NusRESUMO
In this Perspective, we have brought together available biological evidence on hydrazides as histone deacetylase inhibitors (HDACis) and as a distinct type of Zn-binding group (ZBG) to be reviewed for the first time in the literature. N-Alkyl hydrazides have transformed the field, providing innovative and practical chemical tools for selective and effective inhibition of specific histone deacetylase (HDAC) enzymes, in addition to the usual hydroxamic acid and o-aminoanilide ZBG-bearing HDACis. This has enabled efficient targeting of neurodegenerative diseases such as Alzheimer's disease, cancer, cardiovascular diseases, and protozoal pathologies.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Hidrazinas , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Humanos , Hidrazinas/química , Hidrazinas/farmacologia , Hidrazinas/síntese química , Histona Desacetilases/metabolismo , Histona Desacetilases/química , Animais , Zinco/química , Relação Estrutura-AtividadeRESUMO
Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
Assuntos
Cardiotônicos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Piridinas , Humanos , Animais , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Piridinas/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Relação Estrutura-Atividade , Cardiotônicos/farmacologia , Cardiotônicos/química , Cardiotônicos/síntese química , Cardiotônicos/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Masculino , Imidazóis/farmacologia , Imidazóis/química , Imidazóis/síntese química , Imidazóis/uso terapêutico , Camundongos Nus , Descoberta de DrogasRESUMO
HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsis sp. XZB108, selectively inhibited HDAC8 (IC50 = 0.90 ± 0.014 µM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50 = 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5k was at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5k displayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5k triggered antitumor immunity by activating T cells. Treatment with 5k significantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5k represents a promising compound for further investigation as a potential treatment for breast cancer.
Assuntos
Antineoplásicos , Neoplasias da Mama , Inibidores de Histona Desacetilases , Histona Desacetilases , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Conventional chemotherapy, especially with natural anticancer drugs, usually suffers from poor bioavailability and low tumor accumulation. To address these limitations, we developed a novel approach for modifying natural products in which amphiphilic hydroxamic acid hybrids based on a natural product: isoalantolactone (IAL) were rationally designed. Compound 18 is identified as a highly potent dual signal transducer and activator of transcription 3 (STAT3)/histone deacetylases (HDAC) inhibitor and induces autophagy and apoptosis. 18 exhibits higher antitumor potency than IAL and the hydroxamic acid SAHA in vitro and in vivo. Furthermore, 18 self-assembled in water to form nanoparticles (18 NPs), which facilitated the accumulation of drugs in tumor tissues and promoted their cellular uptake, resulting in superior anticancer efficacy compared to free 18. Compared to drug-drug conjugates, hydroxamic acid hybrids have a smaller molecular weight and can synergize with various anticancer drugs. Overall, these findings indicate that 18 utilizing nanomedicines and dual-target drugs provide an efficient strategy for the rational design of dual-target drugs and the modification of natural products.
Assuntos
Antineoplásicos , Apoptose , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos , Nanopartículas , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/síntese química , Nanopartículas/química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Apoptose/efeitos dos fármacos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Camundongos , Estrutura Molecular , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Histona Desacetilases/metabolismo , Lactonas/química , Lactonas/farmacologia , Lactonas/síntese químicaRESUMO
Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 µM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 µM).
Assuntos
Antimaláricos , Inibidores de Histona Desacetilases , Peptoides , Plasmodium falciparum , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Humanos , Antimaláricos/farmacologia , Antimaláricos/química , Antimaláricos/síntese química , Peptoides/farmacologia , Peptoides/química , Peptoides/síntese química , Relação Estrutura-Atividade , Células HEK293 , Testes de Sensibilidade Parasitária , Estrutura Molecular , Relação Dose-Resposta a Droga , Histona Desacetilases/metabolismoRESUMO
Class I histone deacetylases (HDACs) are closely associated with the development of a diverse array of diseases, including cancer, neurodegenerative disorders, HIV, and inflammatory diseases. Considering the essential roles in tumorigenesis, class I HDACs have emerged as highly desirable targets for therapeutic strategies, particularly in the field of anticancer drug development. However, the conventional class I HDAC inhibitors faced several challenges such as acquired resistance, inherent toxicities, and limited efficacy in inhibiting non-enzymatic functions of HDAC. To address these problems, novel strategies have emerged, including the development of class I HDAC dual-acting inhibitors, targeted protein degradation (TPD) technologies such as PROTACs, molecular glues, and HyT degraders, as well as covalent inhibitors. This review provides a comprehensive overview of class I HDAC enzymes and inhibitors, by initially introducing their structure and biological roles. Subsequently, we focus on the recent advancements of class I HDAC modulators, including isoform-selective class I inhibitors, dual-target inhibitors, TPDs, and covalent inhibitors, from the perspectives of rational design principles, pharmacodynamics, pharmacokinetics, and clinical progress. Finally, we also provide the challenges and outlines future prospects in the realm of class I HDAC-targeted drug discovery for cancer therapeutics.
Assuntos
Inibidores de Histona Desacetilases , Histona Desacetilases , Humanos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estrutura Molecular , Animais , Relação Estrutura-AtividadeRESUMO
Alzheimer disease (AD) is the most prevalent form of dementia that develops spontaneously in the elderly. It's worth mentioning that as people age, the epigenetic profile of the central nervous system cells changes, which may speed up the development of various neurodegenerative disorders including AD. Histone deacetylases (HDACs) are a class of epigenetic enzymes that can control gene expression without altering the gene sequence. Moreover, a promising strategy for multi-target hybrid design was proposed to potentially improve drug efficacy and reduce side effects. These hybrids are monocular drugs that contain various pharmacophore components and have the ability to bind to different targets at the same time. The HDACs ability to synergistically boost the performance of other anti-AD drugs, as well as the ease with which HDACs inhibitor cap group, can be modified. This has prompted numerous medicinal chemists to design a novel generation of HDACs multi-target inhibitors. Different HDACs inhibitors and other ones such as acetylcholinesterase, butyryl-cholinesterase, phosphodiesterase 9, phosphodiesterase 5 or glycogen synthase kinase 3ß inhibitors were merged into hybrids for treatment of AD. This review goes over the scientific rationale for targeting HDACs along with several other crucial targets in AD therapy. This review presents the latest hybrids of HDACs and other AD target pharmacophores.
Assuntos
Doença de Alzheimer , Desenho de Fármacos , Inibidores de Histona Desacetilases , Histona Desacetilases , Doença de Alzheimer/tratamento farmacológico , Humanos , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Estrutura Molecular , Animais , Relação Estrutura-AtividadeRESUMO
In recent years, poly(ADP-ribose)polymerase-1 (PARP-1) and histone deacetylase (HDAC) have emerged as significant targets in tumor therapy, garnering widespread attention. In this study, we designed and synthesized two novel phthalazinone PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors, named DLC-1-46 containing dithiocarboxylate fragments and DLC-47-63 containing hydroxamic acid fragments, and evaluated their inhibitory activities on enzymes and cells. Among the PARP-1 inhibitors, most compounds exhibited high inhibitory activity against the PARP-1 enzyme, with DLC-1-6 being particularly notable, showing IC50 values <0.2â¯nM. Notably, DLC-1 demonstrated significant anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells reaching 0.08, 26.39, and 1.01⯵M, respectively. Further investigation revealed that DLC-1 arrested MDA-MB-231 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Among the designed dual PARP-1/HDAC-1 inhibitors, several compounds exhibited potent dual-target inhibitory activity, with DLC-49 displaying IC50 values of 0.53â¯nM and 17â¯nM for PARP-1 and HDAC-1, respectively. DLC-50 demonstrated the most potent anti-proliferative activity, with IC50 values for inhibiting the proliferation of MDA-MB-436, MDA-MB-231, and MCF-7 cells at 0.30, 2.70, and 2.41⯵M, respectively. Cell cycle arrest and apoptosis assays indicated that DLC-50 arrested the cell cycle in the G2 phase and induced apoptosis in HCT-116 cells. Our findings present a novel avenue for further exploration of PARP-1 inhibitors and dual PARP-1/HDAC-1 inhibitors.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 1 , Inibidores de Histona Desacetilases , Ftalazinas , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Ftalazinas/farmacologia , Ftalazinas/síntese química , Ftalazinas/química , Estrutura Molecular , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Simulação de Acoplamento MolecularRESUMO
Our previously reported HDAC6 inhibitor (HDAC6i) Marbostat-100 (4) has provided many arguments for further clinical evaluation. By the substitution of the acidic hydrogen of 4 for different carbon residues, we were able to generate an all-carbon stereocenter, which significantly improves the hydrolytic stability of the inhibitor. Further asymmetric synthesis has shown that the (S)-configured inhibitors preferentially bind to HDAC6. This led to the highly selective and potent methyl-substituted derivative S-29b, which elicited a long-lasting tubulin hyperacetylation in MV4-11 cells. Finally, a crystal structure of the HDAC6/S-29b complex provided mechanistic explanation for the high potency and stereoselectivity of synthesized compound series.
Assuntos
Carbolinas , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Humanos , Carbolinas/química , Carbolinas/farmacologia , Carbolinas/síntese química , Linhagem Celular Tumoral , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Morfolinas/síntese química , Morfolinas/química , Morfolinas/farmacologiaRESUMO
Histone deacetylases (HDACs) are highly attractive targets in the drug development process, and the development of subtype-selective HDAC inhibitors is the research direction for HDAC inhibitors. As an important member of the HDAC family, HDAC3 has been found to be closely related to the pathological progression of many diseases due to its abnormal expression. In previous studies, we discovered compound 13a, which has potent inhibitory activity against HDAC1, 2, and 3. In this work, we improved the HDAC3 isotype selectivity of 13a, and obtained compound 9c through rational drug design. 9c shows a selectivity of 71 fold for HDAC3 over HDAC1 and can significantly inhibit the proliferation activity of MV4-11 cells in vitro. Furthermore, when combined with Venetoclax, 9c can effectively induce apoptosis in MV4-11 cells in vitro and reduce the expression of anti-apoptotic proteins, the development of HDAC3 selective inhibitors may serve as a potential lead compound to reverse Venetoclax resistance.
Assuntos
Antineoplásicos , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases , Histona Desacetilases , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/química , Sulfonamidas/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Apoptose/efeitos dos fármacos , Estrutura Molecular , Linhagem Celular Tumoral , Relação Dose-Resposta a DrogaRESUMO
Targeting the programmed cell death-1/ligand 1 (PD-1/PD-L1) pathway is one of the most promising cancer treatment strategies. Studies have shown that HDAC inhibitors can enhance the antitumor immune response by modulating the expression of PD-L1. Herein, we designed and synthesized a series of novel hydrazide-based small molecule HDAC inhibitors; among them, compound HQ-30 showed selective HDAC3 inhibition (IC50 = 89 nM) and remarkable PD-L1-degrading activity (DC50 = 5.7 µM, Dmax = 80% at 10 µM). Further studies revealed that HQ-30 induced the degradation of PD-L1 by regulating cathepsin B (CTSB) in the lysosomes. Further, HQ-30 could enhance the infiltration of CD3+ CD4+ helper T and CD3+ CD8+ cytotoxic T cells in tumors, thus activating the tumor immune microenvironment. Moreover, HQ-30 possessed a benign toxicity profile (LD50 > 1000 mg/kg) and favorable pharmacokinetic properties (F = 57%). Taken together, HQ-30 is worthy of further investigation as a small molecule-based epigenetic modulator of tumor immunotherapy.
Assuntos
Antineoplásicos , Antígeno B7-H1 , Inibidores de Histona Desacetilases , Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Animais , Histona Desacetilases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/síntese química , Camundongos , Regulação para Baixo/efeitos dos fármacos , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Relação Estrutura-Atividade , Descoberta de Drogas , Catepsina B/antagonistas & inibidores , Catepsina B/metabolismoRESUMO
Soluble epoxide hydrolase (sEH) and HDAC6 mediate the NF-κB pathway in inflammatory responses, and their inhibitors exhibit powerful anti-inflammatory and analgesic activities in treating both inflammation and pain. Therefore, a series of dual-targeting inhibitors containing urea or squaramide and hydroxamic acid moieties were designed and synthesized, and their role as a new sEH/HDAC6 dual-targeting inhibitor in inflammatory pain was evaluated in a formalin-induced mice model and a xylene-induced mouse ear swelling model. Among them, compounds 28g and 28j showed the best inhibitory and selectivity of sEH and HDAC6. Compound 28g had satisfactory pharmacokinetic characteristics in rats. Following administration at 30 mg/kg, compound 28g exhibited more effective analgesic activity than either an sEH inhibitor (GL-B437) or an HDAC6 inhibitor (Rocilinostat) alone and coadministration of both inhibitors. Thus, these novel sEH/HDAC6 dual-targeting inhibitors exhibited powerful analgesic activity in nociceptive behavior and are worthy of further development.
Assuntos
Analgésicos , Desenho de Fármacos , Epóxido Hidrolases , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases , Inflamação , Dor , Animais , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Dor/tratamento farmacológico , Camundongos , Inflamação/tratamento farmacológico , Analgésicos/síntese química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Analgésicos/farmacocinética , Analgésicos/química , Masculino , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/farmacocinética , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , HumanosRESUMO
Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.
Assuntos
Antineoplásicos , Benzofuranos , Proliferação de Células , Ácidos Hidroxâmicos , Moduladores de Tubulina , Tubulina (Proteína) , Humanos , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/síntese química , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/síntese química , Tubulina (Proteína)/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Células HeLa , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/metabolismo , Linhagem Celular Tumoral , Células MCF-7 , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29RESUMO
The design and radiosynthesis of [18F]NT376, a high potency inhibitor of class-IIa histone deacetylases (HDAC) is reported. We utilized a three-step radiochemical approach that led to the radiosynthesis of [18F]NT376 in a good radiochemical yield, (17.0 ± 3%, decay corrected), high radiochemical purity (> 97%) and relatively high molar activity of 185.0 GBq/µmol (> 5.0 Ci/µmol). The repositioning of the 18F-radiolabel into a phenyl ring (18F-Fluoro-aryl) of the class-IIa HDAC inhibitor avoided the shortcomings of the direct radiolabeling of the 5-trifluoromethyl-1,2,4-oxadiazole moiety that was reported by us previously and was associated with low molar activity (0.74-1.51 GBq/µmol, 20-41 mCi/µmol). This radiochemical approach could find a wider application for radiolabeling similar molecules with good radiochemical yield and high molar activity.