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更新于：2025-05-07

HDAC3 inhibitors(Birla Institute of Technology & Science)

更新于：2025-05-07

概要

概要

基本信息

药物类型

小分子化药

别名

Compound 4i(Birla Institute of Technology & Science)

靶点

HDAC3

作用方式

抑制剂

作用机制

HDAC3抑制剂(组蛋白去乙酰化酶3抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病

在研适应症

三阴性乳腺癌

非在研适应症-

原研机构

Birla Institute of Technology & Science

在研机构

Birla Institute of Technology & Science

非在研机构-

权益机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构/序列

分子式C16H21N5O2

InChIKeyUNXQXLFIXZKRCS-UHFFFAOYSA-N

CAS号3033039-28-7

关联

100 项与 HDAC3 inhibitors(Birla Institute of Technology & Science) 相关的临床结果

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100 项与 HDAC3 inhibitors(Birla Institute of Technology & Science) 相关的转化医学

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100 项与 HDAC3 inhibitors(Birla Institute of Technology & Science) 相关的专利（医药）

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143

项与 HDAC3 inhibitors(Birla Institute of Technology & Science) 相关的文献（医药）

2025-07-01·European Journal of Medicinal Chemistry

Design, synthesis and bioevaluation of novel hydrazide derivatives as enhancers of immunotherapy and DNA-damage response in antitumor therapy

Article

作者: Li, Shuqing ; Peng, Xiaopeng ; Pan, Wanyi ; Hu, Zhihao ; Wu, Haiyan

We have designed and synthesized a series of novel hydrazide-based HDAC3 inhibitors, with the representative compound 8ae demonstrating potent HDAC3 inhibitory activity, having an IC₅₀ value of 311 nM (with a selectivity index SI greater than 32 over other HDACs). Compound 8ae also exhibited significant anti-proliferative activity against five types of cancer cells, with an average inhibitory rate IC₅₀ value of 5.036 μM, and was capable of inhibiting the migration, invasion, and wound healing activities of B16-F10 cells. Further studies revealed that 8ae effectively modulates the expression of Ac-H3 within tumor cells and can degrade PD-L1 in tumor cells through the lysosome pathway mediated by cathepsin B (CTSB). Notably, 8ae also possesses favorable pharmacokinetic properties. In in vivo experiments, the combination of 8ae with the PD-L1 inhibitor NP-19 activated the immune system in melanoma-bearing mice, leading to an enhanced anti-tumor immune response (TGI = 65 %). When combined with olaparib, 8ae significantly enhanced tumor suppressive activity (TGI = 88 %) in a breast cancer mouse model and displayed a favorable safety profile. Collectively, 8ae is a promising HDAC3 inhibitor that warrants further exploration in cancer therapeutic strategies.

2025-07-01·European Journal of Medicinal Chemistry

Design and synthesis of pyridine-based benzamides as potent HDAC3 inhibitors as an armament against breast cancer with in vivo validation

Article

作者: Ghosh, Balaram ; Patel, Tarun ; Banerjee, Suvankar ; Pulya, Sravani ; Biswas, Swati ; Routholla, Ganesh ; Adhikari, Nilanjan ; Begum, Darakhshan ; Himaja, Ambati ; Regula, Sanjeev

Some novel benzamide derivatives with modified linker group were designed and synthesized as promising HDAC3-selective inhibitors. These compounds exerted promising antiproliferative potential compared to reference molecule CI994 while tested against several cancer cell lines. Notably, all these molecules exhibited nontoxicity towards normal human cell lines. The most promising molecule in series 7c exhibited ∼47-fold HDAC3 selectivity over HDAC2 isoform. Compound 7c induced apoptosis and cell cycle arrest in the G2/M phase in the 4T1 cell line. Moreover, compound 7c yielded a good in vivo pharmacokinetic profile. Notably, compound 7c markedly reduced tumor growth in the 4T1-Luc breast cancer xenograft model in female Balb/c mice. Compound 7c also upregulated apoptotic proteins namely caspase-3, caspase-7, and cytochrome c, and downregulated Bcl-2. The antitumor potential of compound 7c was further justified by the downregulation of EGFR and Ki-67 through Western blot analysis. Nevertheless, the HDAC3 inhibitory potency of compound 7c depicted strong and stable binding interaction at the HDAC3 active site. These findings validated that compound 7c is a promising HDAC3 inhibitor that can be further investigated for clinical translation to achieve emerging breast cancer therapeutics.

2025-05-01·Biophysical Chemistry

A semiempirical and machine learning approach for fragment-based structural analysis of non-hydroxamate HDAC3 inhibitors

Article

作者: Sessa, Lucia ; Gayen, Shovanlal ; Tarafdar, Rajdip ; Amin, Sk Abdul ; Piotto, Stefano

Interest in HDAC3 inhibitors (HDAC3i) for pharmacological applications outside of cancer is growing. However, concerns regarding the possible mutagenicity of the commonly used hydroxamates (zinc-binding groups, ZBGs) are also increasing. Considering these concerns, non-hydroxamate ZBGs offer a promising alternative for the development of non-mutagenic HDAC3 inhibitors. Unfortunately, the quantum chemical space of non-hydroxamates has not been studied in detail. This study has three primary goals: (i) to perform semiempirical quantum chemical calculations, examining AM-1 model parameters relevant to zinc binding, (ii) to develop supervised mathematical learning models to train a diverse set of non-hydroxamate-based HDAC3i, and (iii) to apply fragment-based approaches to identify sub-structural fragments (fingerprints) that promote or hinder HDAC3 inhibitory activity through classification-based QSARs. In addition, flexible molecular docking analysis, 200 ns MD simulation, and free energy landscape (FEL) analysis further established the importance of identified fingerprints in the modulation of HDAC3 inhibitory activity. This comprehensive analysis of structural variations among non-hydroxamate HDAC3i provides valuable insights, contributing to the design of potential non-mutagenic HDAC3i.

100 项与 HDAC3 inhibitors(Birla Institute of Technology & Science) 相关的药物交易

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