The
metabolic enzyme methionine adenosyltransferase 2A (MAT2A)
was recently implicated as a synthetic lethal target in cancers with
deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor
and codeleted with CDKN2A in approximately 15% of
all cancers. Previous attempts to target MAT2A with small-molecule
inhibitors identified cellular adaptations that blunted their efficacy.
Here, we report the discovery of highly potent, selective, orally
bioavailable MAT2A inhibitors that overcome these challenges. Fragment
screening followed by iterative structure-guided design enabled >10 000-fold
improvement in potency of a family of allosteric MAT2A inhibitors
that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme’s active
site. We demonstrate that potent MAT2A inhibitors substantially reduce
SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors.
These data supported progressing AG-270 into current
clinical studies ( NCT03435250).
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