Design, Synthesis, and Biological Evaluation of a Series of Spiro Analogues as Novel HPK1 Inhibitors

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-10-30 DOI:10.1021/acsmedchemlett.4c0043410.1021/acsmedchemlett.4c00434

Jingjing Peng, Xiaoyu Ding, Celia X. J. Chen, Pei-Yu Shih, Qingyuan Meng, Xiao Ding, Man Zhang, Alex Aliper, Feng Ren, Hongfu Lu* and Alex Zhavoronkov*,

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Abstract

Hematopoietic progenitor kinase 1 (HPK1) negatively affects T cell activation and proliferation and is a promising target for immunotherapy. Although HPK1 inhibitors have shown promising efficacy in preclinical models, none have been approved for clinical use. One significant challenge in developing an HPK1 inhibitor is the difficulty in designing a potent inhibitor with good kinase selectivity and pharmacokinetic properties. Here, we report a series of spiro HPK1 inhibitors with good potency and selectivity. Specifically, compound 16 exhibited potent HPK1 inhibition (IC₅₀ = 2.67 nM), adequate selectivity toward the MAP4K family (>100-fold), and good selectivity against selected kinases (>300-fold). Compound 16 demonstrated moderate in vivo clearance and reasonable oral exposure in mice and rats. Notably, compound 16 possessed good antitumor efficacy in the CT26 murine colon cancer and a synergistic effect when combined with anti-PD-1. These exciting preclinical results support the continued development of this class of HPK1 inhibitors.

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作为新型 HPK1 抑制剂的一系列螺环类似物的设计、合成和生物学评价

造血祖细胞激酶 1（HPK1）会对 T 细胞的活化和增殖产生负面影响，是一种很有前景的免疫疗法靶点。虽然 HPK1 抑制剂在临床前模型中显示出良好的疗效，但还没有一种被批准用于临床。开发 HPK1 抑制剂的一个重大挑战是很难设计出具有良好激酶选择性和药代动力学特性的强效抑制剂。在此，我们报告了一系列具有良好效力和选择性的螺 HPK1 抑制剂。具体来说，化合物 16 对 HPK1 具有强效抑制作用（IC50 = 2.67 nM），对 MAP4K 家族具有充分的选择性（100 倍），对特定激酶具有良好的选择性（300 倍）。化合物 16 在小鼠和大鼠体内表现出中等的体内清除率和合理的口服暴露。值得注意的是，化合物 16 在 CT26 小鼠结肠癌中具有良好的抗肿瘤疗效，与抗-PD-1 结合使用时还会产生协同效应。这些令人振奋的临床前研究结果为继续开发这类 HPK1 抑制剂提供了支持。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.