Vara Brandon A, Levi Samuel M, Achab Abdelghani, Candito David A, Fradera Xavier, Lesburg Charles A, Kawamura Shuhei, Lacey Brian M, Lim Jongwon, Methot Joey L, Xu Zangwei, Xu Haiyan, Smith Dustin M, Piesvaux Jennifer A, Miller J Richard, Bittinger Mark, Ranganath Sheila H, Bennett David J, DiMauro Erin F, Pasternak Alexander
Discovery Chemistry, Computational and Structural Chemistry, Quantitative Biosciences, Pharmacokinetics and Drug Metabolism, Oncology Early Discovery, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
ACS Med Chem Lett. 2021 Mar 19;12(4):653-661. doi: 10.1021/acsmedchemlett.1c00096. eCollection 2021 Apr 8.
Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase, is a negative immune regulator of T cell receptor (TCR) and B cell signaling that is primarily expressed in hematopoietic cells. Accordingly, it has been reported that HPK1 loss-of-function in HPK1 kinase-dead syngeneic mouse models shows enhanced T cell signaling and cytokine production as well as tumor growth inhibition , supporting its value as an immunotherapeutic target. Herein, we present the structurally enabled discovery of novel, potent, and selective diaminopyrimidine carboxamide HPK1 inhibitors. The key discovery of a carboxamide moiety was essential for enhanced enzyme inhibitory potency and kinome selectivity as well as sustained elevation of cellular IL-2 production across a titration range in human peripheral blood mononuclear cells. The elucidation of structure-activity relationships using various pendant amino ring systems allowed for the identification of several small molecule type-I inhibitors with promising profiles.
造血祖细胞激酶1（HPK1）是一种丝氨酸/苏氨酸激酶，是T细胞受体（TCR）和B细胞信号传导的负性免疫调节因子，主要在造血细胞中表达。因此，有报道称，在HPK1激酶失活的同基因小鼠模型中，HPK1功能丧失表现出增强的T细胞信号传导和细胞因子产生以及肿瘤生长抑制，支持其作为免疫治疗靶点的价值。在此，我们展示了基于结构发现的新型、强效和选择性二氨基嘧啶甲酰胺类HPK1抑制剂。甲酰胺部分的关键发现对于增强酶抑制效力和激酶组选择性以及在人外周血单核细胞的滴定范围内持续提高细胞白细胞介素-2的产生至关重要。使用各种侧链氨基环系统阐明构效关系，使得能够鉴定出几种具有良好特性的小分子I型抑制剂。
