The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.

中文翻译：

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取代喹啉-5,8-二酮作为有效 NSD2 抑制剂的结构修饰和药理学评价

组蛋白赖氨酸甲基转移酶 NSD2 在多种类型的癌症中过度表达、易位或突变，并已成为一个有吸引力的治疗靶点。然而，小分子 NSD2 抑制剂的开发仍处于起步阶段，非常需要选择性和有效的 NSD2 抑制剂。在此，鉴于报道的NSD2抑制剂DA3003-1的结构新颖性，我们基于喹啉-5,8-二酮支架进行了全面的结构优化。鉴定出化合物15a在细胞中具有高 NSD2 抑制活性和有效的抗增殖作用。同时，化合物15a具有优异的药代动力学特征和高口服生物利用度。此外，该化合物被发现在多发性骨髓瘤异种移植小鼠模型中显示出显着的抗肿瘤功效和理想的安全性，因此有理由将其作为进一步研究的有希望的候选者。