jm3c01860_si_001.pdf (3.97 MB)
Development of a Series of Pyrrolopyridone MAT2A Inhibitors
Version 2 2024-03-13, 18:16
Version 1 2024-03-11, 17:09
journal contribution
posted on 2024-03-13, 18:16 authored by Stephen J. Atkinson, Sharan K. Bagal, Argyrides Argyrou, Sean Askin, Tony Cheung, Elisabetta Chiarparin, Muireann Coen, Iain T. Collie, Ian L. Dale, Claudia De Fusco, Keith Dillman, Laura Evans, Lyman J. Feron, Alison J. Foster, Michael Grondine, Vasudev Kantae, Gillian M. Lamont, Scott Lamont, James T. Lynch, Sten Nilsson Lill, Graeme R. Robb, Jamal Saeh, Marianne Schimpl, James S. Scott, James Smith, Bharath Srinivasan, Sharon Tentarelli, Mercedes Vazquez-Chantada, David Wagner, Jarrod J. Walsh, David Watson, Beth WilliamsonThe
optimization of an allosteric fragment, discovered by differential
scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed.
The structure-based drug discovery approach, aided by relative binding
free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic
properties. This tool showed a selective antiproliferative effect
on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro
and in vivo, providing further evidence to support the utility of
MAT2a inhibitors as potential anticancer therapies for MTAP-deficient
tumors.
