Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors

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.