Hematopoietic progenitor kinase 1 (HPK1/MAP4K1) represents a high interest target for the treatment of cancer through an immune-mediated mechanism. Herein we present highlights of the drug discovery campaign within the lactam/azalactam series of inhibitors that yielded a small molecule (21, PF-07265028), which was advanced to a phase 1 clinical trial (NCT05233436). Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1.

中文翻译：

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PF-07265028 的发现，PF-07265028 是一种用于治疗癌症的造血祖细胞激酶 1 （HPK1） 的选择性小分子抑制剂


造血祖细胞激酶 1 （HPK1/MAP4K1） 代表通过免疫介导机制治疗癌症的高关注靶点。在此，我们介绍了内酰胺/氮内酰胺类抑制剂中药物发现活动的亮点，该抑制剂产生了一个小分子 （21， PF-07265028），该分子已进入 1 期临床试验 （NCT05233436）。发现工作的关键组成部分包括通过使用共晶结构指导通过减轻配体应变来优化效力，减轻 ADME 负荷（CYP2D6 的血浆不稳定性和馏分代谢）以及激酶选择性的优化，特别是对与 HPK1 高度同源的免疫调节激酶。事实证明，通过利用共晶结构和亲脂性效率分析进行基于结构的药物设计是有价值的工具，最终能够递送临床质量的 HPK1 小分子抑制剂。