Discovery of Novel Spirocyclic MAT2A Inhibitors Demonstrating High In Vivo Efficacy in MTAP-Null Xenograft Models

Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of S-methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design. The Hit compound 9 exhibited high potency in enzymatic activity (IC₅₀ = 7 nM) and in HCT-116 MTAP^(-/-) cell potency (IC₅₀ = 17 nM). Further optimization has led to the identification of two new lead compounds: a brain-penetrant compound, 29-1, and a potent but limited brain-penetrant compound, 39. Both of these lead compounds demonstrate increased plasma drug exposure and exhibit significant efficacy in xenograft models that are depleted of MTAP. We hope that identifying a brain-penetrant MAT2A inhibitor will create new opportunities to explore the potential therapeutic effects of S-adenosylmethionine modulation in the central nervous system.