6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-的发现3,4-dihydropyrimidin-4-one (IACS-15414)，一种有效的口服生物可利用的 SHP2 抑制剂,Journal of Medicinal Chemistry

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6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-的发现3,4-dihydropyrimidin-4-one (IACS-15414)，一种有效的口服生物可利用的 SHP2 抑制剂
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-13 , DOI: 10.1021/acs.jmedchem.1c01132
Barbara Czako ₁ , Yuting Sun ₂ , Timothy McAfoos ₁ , Jason B Cross ₁ , Paul G Leonard ₁ , Jason P Burke ₁ , Christopher L Carroll ₁ , Ningping Feng ₂ , Angela L Harris ₂ , Yongying Jiang ₁ , Zhijun Kang ₁ , Jeffrey J Kovacs ₂ , Pijus Mandal ₁ , Brooke A Meyers ₂ , Faika Mseeh ₁ , Connor A Parker ₁ , Simon S Yu ₁ , Christopher C Williams ₁ , Qi Wu ₁ , Maria Emilia Di Francesco ₁ , Giulio Draetta ₃ , Timothy Heffernan ₂ , Joseph R Marszalek ₂ , Nancy E Kohl ₄ , Philip Jones ₁

Affiliation

Src 同源 2 (SH2) 含磷酸酶 2 (SHP2) 域在受体酪氨酸激酶 (RTK)、神经纤维蛋白-1 (NF-1) 和克尔斯滕大鼠肉瘤病毒 (KRAS) 突变驱动的癌症中起作用，以及在 RTK 介导的抗性中，使得鉴定干扰其功能的小分子疗法备受关注。我们寻找有效的、口服生物可利用的和安全的 SHP2 抑制剂的探索导致发现了一系列有前途的吡唑并嘧啶酮，它们表现出优异的效力，但在体内表现不佳药代动力学（PK）概况。假设驱动的支架优化使我们获得了一系列具有优异跨物种 PK 特性但人类 Ether-à-go-go-Related Gene (hERG) 窗口的吡唑并吡嗪。随后的特性优化导致了嘧啶酮系列的发现，其中多个成员具有出色的效力、跨物种的最佳体内PK，并且没有脱靶活性，包括高达 100 μM 的无 hERG 责任。重要的是，化合物30 (IACS-15414)在体内RTK 激活和 KRAS ^mut异种移植模型中有效抑制丝裂原活化蛋白激酶 (MAPK) 通路信号传导和肿瘤生长。

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Discovery of 6-[(3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRAS^mut xenograft models in vivo.

更新日期：2021-10-28

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