Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China.
J Med Chem. 2023 Oct 12;66(19):13646-13664. doi: 10.1021/acs.jmedchem.3c00992. Epub 2023 Sep 27.
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 with potent SHP2 inhibitory activity (IC = 17.7 nM) effectively inhibited the proliferation, migration, and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, compound featured great in vivo pharmacokinetic properties (AUC = 4320 nM·h; = 66.3%) and exhibited significant antitumor efficacy in the MIA PaCa-2 xenograft mouse model. This demonstrates that compound 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.
Src 同源物-2 结构域包含蛋白酪氨酸磷酸酶-2（SHP2）是治疗 Kirsten 大鼠肉瘤病毒癌基因（KRAS）突变型癌症的极具吸引力的治疗靶点。在这项工作中，通过虚拟筛选和合理的结构优化，发现了一系列胍基 SHP2 别构抑制剂。值得注意的是，先导化合物 具有很强的 SHP2 抑制活性（IC = 17.7 nM），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 在体内具有良好的药代动力学特性（AUC = 4320 nM·h； = 66.3%），并在 MIA PaCa-2 异种移植小鼠模型中表现出显著的抗肿瘤疗效。这表明化合物 是开发 SHP2 别构抑制剂治疗 KRAS 突变型癌症的潜在先导化合物。此外，这些胍基骨架可能为减轻当前 SHP2 别构抑制剂中主要包含的烷基胺基序的潜在安全风险提供机会。
