Shanghai Haiyan Pharmaceutical Technology Co Ltd

Chiral discrimination of amino acid stereoisomers is essential for biological processes and pharmaceutical development. Bisporphyrins represent promising candidates for the chiral recognition of amino acid derivatives. Herein, we report a rationally designed binaphthyl-linked zinc bisporphyrinate complex demonstrating remarkable enantioselective binding toward l-phenylglycine ethyl ester (L-PhgOEt). The complex demonstrates a 19-fold amplification in circular dichroism (CD) response intensity for L-PhgOEt over its d-enantiomer, with quantified enantioselectivity (L/D = 4.8), reflecting good chiral recognition capabilities. Single-crystal X-ray analysis unveils a multimodal recognition mechanism involving (i) axial coordination to zinc centers, (ii) hydrogen bonding interactions with amide functionalities, and (iii) π-system stabilization through both C–H···π and O···π interactions with the methoxy-functionalized binaphthyl linker. This synergistic combination of coordination bonds and noncovalent interactions establishes bisporphyrins as tailorable chiral receptors and guides the design of biomimetic systems for pharmaceutical applications.

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.