Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-c]quinolin-4-one skeleton based on structure-based drug design. Further optimization led to compound 39, which has a high potency for inhibiting MAT2A and a remarkable selectivity for MTAP-deleted cancer cell lines. Compound 39 has a favorable pharmacokinetic profile with high plasma exposure and oral bioavailability, and it exhibits significant efficacy in xenograft MTAP-depleted models. Moreover, 39 demonstrates excellent brain exposure with a K_puu of 0.64 in rats.

中文翻译：

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具有高选择性、脑渗透性和体内功效的蛋氨酸腺苷转移酶 2A (MAT2A) 抑制剂的基于结构的设计和优化


合成致死最近已成为治疗以前被认为无法成药的突变基因的新方法。通过删除甲硫腺苷磷酸化酶 (MTAP) 基因来靶向癌症中的甲硫氨酸腺苷转移酶 2A (MAT2A) 可导致合成致死性，因此引起了精准抗癌药物开发领域的极大兴趣。在此，我们报告了基于结构药物设计的一系列新型 MAT2A 抑制剂的发现，这些抑制剂具有吡唑并[3,4-c]喹啉-4-酮骨架。进一步优化得到了化合物 39，它具有高效抑制 MAT2A 的功效，并且对 MTAP 缺失的癌细胞系具有显着的选择性。化合物 39 具有良好的药代动力学特征、高血浆暴露量和口服生物利用度，并且在异种移植 MTAP 耗尽模型中表现出显着的功效。此外，39 在大鼠中表现出出色的大脑暴露，K _puu 为 0.64。