Improved Pharmacokinetic Profiles of HDAC6 Inhibitors via Cap Group Modifications

Hydroxamic acid (HA)-based HDAC inhibitors often suffer from poor pharmacokinetic (PK) profiles, limiting their in vivo applications. Cap group modification offers a promising strategy to address these challenges. Here, we optimized the cap group of TO-317, a selective HDAC6 inhibitor with a bisected cap structure, generating 26 analogs with comparable or improved HDAC6 binding affinity and selectivity. Replacing the redundant tetrafluorobenzene sulfonamide cap while retaining the essential picolyl cap group preserved the critical H614 hydrogen bond, as confirmed by X-ray crystallography (1.24–1.27 Å resolution) of five analogs. Analog 14, featuring a 2-chlorobenzene sulfonamide cap, demonstrated a 120-fold enhancement in plasma concentration in mice compared to that of TO-317. Preclinical studies showed that analog 14 achieved 56% tumor growth inhibition in an SM1 melanoma murine model without observed toxicity. These findings highlight cap group optimization as a powerful approach to enhance HA-based HDAC inhibitors for advanced preclinical and clinical development.基于羟肟酸（Hydroxamic acid, HA）的组蛋白去乙酰化酶（HDAC）抑制剂往往存在药代动力学（pharmacokinetic, PK）特性欠佳的问题，进而限制了其体内应用。帽基团修饰为解决上述挑战提供了颇具前景的策略。本研究针对具有双分帽结构的选择性HDAC6抑制剂TO-317的帽基团进行优化，成功合成26个类似物，这些类似物的HDAC6结合亲和力与选择性与原型相当甚至有所提升。研究团队在保留关键吡啶甲基（picolyl）帽基团的前提下，替换冗余的四氟苯磺酰胺帽结构，该修饰保留了至关重要的H614氢键，这一结论通过5个类似物的X射线晶体学分析（分辨率为1.24~1.27 Å）得以证实。带有2-氯苯磺酰胺帽的类似物14，其小鼠体内血浆浓度较TO-317提升了120倍。临床前研究结果显示，类似物14在SM1黑色素瘤小鼠模型中实现了56%的肿瘤生长抑制率，且未观察到明显毒性反应。上述研究结果表明，帽基团优化是提升基于HA的HDAC抑制剂性能的有效手段，可为其后续高级临床前与临床开发提供重要支撑。