J Med Chem. 2019 Feb 28;62(4):1793-1802. doi: 10.1021/acs.jmedchem.8b01726. Epub 2019 Feb 16.
Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.
蛋白酪氨酸磷酸酶 SHP2 是一种癌蛋白，同时也是一种潜在的免疫调节剂，因为它在程序性细胞死亡 PD-L1/PD-1 途径中发挥作用。在前面的手稿中，我们描述了融合双环筛选命中物的优化，以提高效力、选择性和物理化学性质，从而进一步扩大变构 SHP2 抑制剂的化学多样性。在本手稿中，我们描述了我们方法的进一步扩展，通过对 SAR 的理解和基于结构的设计，将融合的双环系统转化为新型单环嘧啶酮支架。这些研究导致了 SHP394（1）的鉴定，这是一种有效的 SHP2 抑制剂，具有高脂溶性效率、提高的效力和增强的药代动力学特性。我们还报告了其他具有良好药代动力学和效力特征的嘧啶酮类似物。总的来说，这项工作改进了我们之前描述的变构抑制剂，并举例说明了和扩展了通过变构机制抑制 SHP2 的允许的化学模板的范围。
