基于2,4-二取代嘧啶骨架的具有免疫调节特性、用于缓解T细胞衰竭的高效且选择性HPK1抑制剂的发现。
Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.
发表日期：2023 Jul 10
作者：
Shenxin Zeng, Ming Zeng, Shuai Yuan, Liuxun He, Yuyuan Jin, Jiandong Huang, Manxuan Zhang, Menghan Yang, Youlu Pan, Zunyuan Wang, Yinqiao Chen, Xiangwei Xu, Wenhai Huang
来源：
BIOORGANIC CHEMISTRY
摘要：
血液造血祖细胞激酶1（HPK1）是丝氨酸/苏氨酸（SER/THR）激酶家族中的一员，属于丝氨酸/苏氨酸（SER/THR）激酶，并已被证明为T细胞受体信号传导的负调节因子。靶向HPK1被认为是一种吸引人的免疫肿瘤治疗策略。在这里，我们描述了基于2,4-二取代嘧啶基团的强力HPK1抑制剂的发现和结构活性关系（SAR）。系统的SAR探索提供了期望的化合物HMC-H8（F1），具有强力的HPK1抑制活性（IC50 = 1.11 nM）和高度选择性。化合物HMC-H8在体外实验中还表现出对p-SLP 76的强力抑制作用（IC50 = 283.0 nM）和促进IL-2释放（EC50 = 157.08 nM），以及INF-γ的剂量依赖性产生。令人惊讶的是，HMC-H8在免疫抑制条件下展现出有效的免疫逆转反应。此外，化合物HMC-H8在人类肝微粒体中表现出可接受的代谢稳定性（T1/2 = 56.87 min），并且对CYP450的抑制较低，以及在大鼠体内良好的口服生物利用度（F = 15.05%）。此外，通过Western blotting实验发现，HMC-H8可调节c-Myc的表达。综上所述，本研究提供了新的强力HPK1抑制剂，以便基于免疫肿瘤进行进一步的抗癌药物发现。版权所有 © 2023 Elsevier Inc. All rights reserved.
Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.Copyright © 2023 Elsevier Inc. All rights reserved.