Ali Khan Hashim, Sharma Chiranjeev, Oh Yong Jin, Yu Ji Hoon, Kim Soong-Hyun, Lee Heejin, Seo Young Ho
College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu, Republic of Korea.
Mol Pharmacol. 2025 Aug;107(8):100062. doi: 10.1016/j.molpha.2025.100062. Epub 2025 Jul 17.
The development of isoform-selective histone deacetylase (HDAC) inhibitors offers a promising approach to minimize the adverse effects of nonselective HDAC inhibitors. HDAC6, due to its unique structural and functional properties, regulates critical cellular processes like gene expression, proliferation, senescence, and apoptosis. Inspired by a tryptoline-derived natural product, callophycin A, a series of compounds were synthesized and evaluated for HDAC6 selectivity. In the HDAC enzyme assay, compound 6a stood out as the lead, demonstrating 21-fold higher potency against HDAC6 compared with HDAC1 (HDAC6 IC = 83.6 ± 1.1 nM vs HDAC1 IC = 1790 ± 1.0 nM). In dose-dependent western blot experiments using H1975 lung cancer cells, a lower concentration of compound 6a (3 μM) induced significantly greater acetylation of α-tubulin compared with histone H3, indicating preferential inhibition of cytoplasmic HDAC6 over the nuclear HDAC1 isoform. Molecular docking of compound 6a at the HDAC6 active site (PDB code: 5EDU) revealed key interactions including π-alkyl contacts via the cap group, π-π stacking through the linker, hydrogen bonding involving the zinc-binding group, and Zn chelation by the hydroxamic acid moiety that support its strong and selective binding, consistent with its HDAC6 inhibitory profile. Overall, compound 6a represents a promising prototype for the rational design of selective HDAC6 inhibitors, offering a structural framework for developing safer and more effective therapeutics aimed at HDAC6-driven cancers, thereby advancing targeted drug development in oncology. SIGNIFICANCE STATEMENT: Selective histone deacetylase 6 (HDAC6) inhibitors provide a safer alternative to nonselective HDAC inhibitors, with potential applications in cancer. This study identifies compound 6a as a promising lead with remarkable HDAC6 specificity, offering a foundation for developing targeted and efficient therapeutics.
亚型选择性组蛋白去乙酰化酶（HDAC）抑制剂的开发为最大限度减少非选择性HDAC抑制剂的不良反应提供了一种有前景的方法。HDAC6因其独特的结构和功能特性，可调节基因表达、增殖、衰老和凋亡等关键细胞过程。受一种源自色胺酮的天然产物卡拉霉素A的启发，合成了一系列化合物并评估其对HDAC6的选择性。在HDAC酶活性测定中，化合物6a表现突出，对HDAC6的效力比对HDAC1高21倍（HDAC6的IC50 = 83.6±1.1 nM，而HDAC1的IC50 = 1790±1.0 nM）。在使用H1975肺癌细胞进行剂量依赖性蛋白质印迹实验中，与组蛋白H3相比，较低浓度的化合物6a（3 μM）诱导α-微管蛋白的乙酰化显著增加，表明与核HDAC1亚型相比，化合物6a对细胞质HDAC6具有优先抑制作用。化合物6a在HDAC6活性位点（PDB编号：5EDU）的分子对接显示了关键相互作用，包括通过帽基团的π-烷基接触、通过连接子的π-π堆积、涉及锌结合基团的氢键以及异羟肟酸部分对锌的螯合，这些相互作用支持其强结合和选择性结合，与其HDAC6抑制谱一致。总体而言，化合物6a是合理设计选择性HDAC6抑制剂的有前景的原型，为开发针对HDAC6驱动癌症的更安全、更有效的治疗方法提供了结构框架，从而推动肿瘤学中的靶向药物开发。意义声明：选择性组蛋白去乙酰化酶6（HDAC6）抑制剂为非选择性HDAC抑制剂提供了更安全的替代方案，在癌症治疗中具有潜在应用。本研究确定化合物6a是一种有前景的先导化合物，具有显著的HDAC6特异性，为开发靶向高效治疗方法奠定了基础。
