Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers,Journal of Medicinal Chemistry

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Identification of a Novel, Potent, and Orally Bioavailable Guanidine-Based SHP2 Allosteric Inhibitor from Virtual Screening and Rational Structural Optimization for the Treatment of KRAS Mutant Cancers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-09-27 , DOI: 10.1021/acs.jmedchem.3c00992
Qiangqiang Hou _{1,

2} , Wenhua Jiang _{1,

2} , Wenqiang Li _{1,

2} , Chenyang Huang _{1,

2} , Kexin Yang _{1,

2} , Xiaoyu Chen _{1,

2} , Mengchen Huang _{1,

2} , Chengxia Shu _{1,

2} , Guangmei Luo _{1,

2} , Haopeng Sun _{1,

3,

4} , Qian Chu _{1,

3} , Xiaoxing Wu _{1,

2}

Affiliation

Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) is a highly attractive therapeutic target for treating Kirsten rat sarcoma viral oncogene (KRAS) mutant cancers. In this work, a series of guanidine-based SHP2 allosteric inhibitors were discovered via virtual screening and rational structural optimization. Notably, lead compound 23 with potent SHP2 inhibitory activity (IC₅₀ = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound 23 featured great in vivo pharmacokinetic properties (AUC_po = 4320 nM·h; F = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 23 is a potential lead compound for the development of SHP2 allosteric inhibitors to treat KRAS mutant cancers. Moreover, these guanidine-based scaffolds may provide an opportunity to mitigate the potential safety risks of the alkyl amine motif predominately incorporated in current SHP2 allosteric inhibitors.

中文翻译：

通过虚拟筛选和合理结构优化鉴定一种新型、有效、口服生物可利用的基于胍的 SHP2 变构抑制剂，用于治疗 KRAS 突变癌症

含有蛋白酪氨酸磷酸酶 2 (SHP2) 的 Src 同源 2 结构域是治疗 Kirsten 大鼠肉瘤病毒癌基因 (KRAS) 突变癌症的极具吸引力的治疗靶点。本工作通过虚拟筛选和合理的结构优化，发现了一系列基于胍的SHP2变构抑制剂。值得注意的是，具有有效 SHP2 抑制活性 (IC ₅₀ = 17.7 nM) 的先导化合物23可有效抑制 MIA PaCa-2 胰腺癌细胞的增殖、迁移和侵袭。此外，化合物23具有良好的体内药代动力学特性（AUC _po = 4320 nM·h；F = 66.3%），并在MIA PaCa-2异种移植小鼠模型中表现出显着的抗肿瘤功效。这表明化合物23是开发治疗 KRAS 突变癌症的 SHP2 变构抑制剂的潜在先导化合物。此外，这些基于胍的支架可能提供一个机会来减轻目前SHP2变构抑制剂中主要掺入的烷基胺基序的潜在安全风险。

更新日期：2023-09-27

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