Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3,ACS Medicinal Chemistry Letters

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Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-12-02 , DOI: 10.1021/acsmedchemlett.0c00517
Ryan A Brawn ₁ , Andrew Cook ₁ , Kiyoyuki Omoto ₁ , Jiyuan Ke ₁ , Craig Karr ₁ , Federico Colombo ₁ , Milena Virrankoski ₁ , Sudeep Prajapati ₁ , Dominic Reynolds ₁ , David M Bolduc ₁ , Tuong-Vi Nguyen ₁ , Patricia Gee ₁ , Deanna Borrelli ₁ , Benjamin Caleb ₁ , Shihua Yao ₁ , Sean Irwin ₁ , Nicholas A Larsen ₁ , Anand Selvaraj ₁ , Xuesong Zhao ₁ , Stephanos Ioannidis ₁

Affiliation

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.

中文翻译：

发现氨基吡唑衍生物作为野生型和看门人突变体 FGFR2 和 3 的有效抑制剂

成纤维细胞生长因子受体 (FGFR) 2 和 3 已被确定为多种癌症的驱动因素，多种药物已获批准或进入后期临床试验。当前抑制剂的一个限制是易受看门人抗性突变的影响。结合靶向高通量筛选和基于结构的药物设计，我们开发了一系列基于氨基吡唑的 FGFR 抑制剂，它们共价靶向激酶 P 环上的半胱氨酸残基。抑制剂对酶的野生型和守门人突变版本表现出优异的活性。使用 SAR 分析和基于结构的药物设计进一步优化导致类似物具有改进的效力以及药物代谢和药代动力学特性。

更新日期：2021-01-14

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