Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India.
Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani Hyderabad Campus, Shamirpet, Hyderabad 500078, India.
J Med Chem. 2023 Sep 14;66(17):12033-12058. doi: 10.1021/acs.jmedchem.3c00614. Epub 2023 Sep 3.
HDAC3 modulation shows promise for breast cancer, including triple-negative cases. Novel -hydrazide-based HDAC3 inhibitors were designed and synthesized. Lead compound exhibited potent HDAC3 inhibition (IC = 14 nM) with at least 121-fold selectivity. It demonstrated strong cytotoxicity against triple-negative breast cancer cells (IC: 0.55 μM for 4T1, 0.74 μM for MDA-MB-231) with least normal cell toxicity. Metabolically stable displayed a superior pharmacokinetic profile. A dose-dependent therapeutic efficacy of was observed in a tumor-bearing mouse model. The biomarker analysis with tumor tissues displayed enhanced acetylation on -H3K9, -H3K27, and -H4K12 compared to -tubulin and -SMC3 indicating HDAC3 selectivity of in vivo. The immunoblotting study with tumor tissue showed upregulation of apoptotic proteins caspase-3, caspase-7, and cytochrome and the downregulation of proliferation markers Bcl-2, CD44, EGFR, and Ki-67. Compound represents a promising candidate for targeted breast cancer therapy, particularly for cases with triple-negative breast cancer.
HDAC3 调节在乳腺癌中显示出前景，包括三阴性病例。设计并合成了新型基于酰腙的 HDAC3 抑制剂。先导化合物 对 HDAC3 具有很强的抑制作用（IC = 14 nM），选择性至少为 121 倍。它对三阴性乳腺癌细胞（IC：4T1 为 0.55 μM，MDA-MB-231 为 0.74 μM）具有很强的细胞毒性，而对正常细胞的毒性最小。代谢稳定的 显示出优越的药代动力学特征。在荷瘤小鼠模型中观察到 的剂量依赖性治疗效果。与 -微管蛋白和 -SMC3 相比，肿瘤组织中的生物标志物分析显示出 -H3K9、-H3K27 和 -H4K12 的乙酰化增强，表明 在体内具有 HDAC3 的选择性。肿瘤组织的免疫印迹研究显示凋亡蛋白 caspase-3、caspase-7 和细胞色素 的上调，以及增殖标志物 Bcl-2、CD44、EGFR 和 Ki-67 的下调。化合物 代表了针对乳腺癌治疗的有前途的候选药物，特别是对三阴性乳腺癌病例。
