Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.

Publication Type:

Journal Article


RSC Med Chem, Volume 13, Issue 12, p.1549-1564 (2022)


<p>Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of -deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.</p>

1 (PDB 8CSG) 3 (PDB SCTB), 4 (PDB 7UYF), 5 (PDB 7UY1), 7 (PDB 7ZVL), 9 (PDB 4X61), 18 (PDB 7ZUP) 22 (PDB 7ZV2), 25 (PDB 7ZVU), 26 (PDB 7ZUY) and 34 (PDB 7ZUU) bound to PRMT5·MTA