Fragment-Based Discovery and Structure-Led Optimization of MSC778, the First Potent, Selective, and Orally Bioavailable FEN1 Inhibitor

Flap endonuclease 1 (FEN1) is a long-standing
target
of interest
in the DNA damage response (DDR) field due to its therapeutic potential
in BRCA mutant cancers. To-date there have only been
a handful of FEN1 inhibitors reported in the literature, most of which
display modest selectivity and/or weak cellular activity. As such,
there is a need for more advanced pharmacological tools to probe the
biology of FEN1. Here, we report the discovery of MSC778, the first potent, selective, and orally bioavailable FEN1 inhibitor.
We describe our metal-chelating fragment screening approach and structure-based
optimization to identify MSC778, using structural insights
to drive design. Consistent with FEN1 inhibition, MSC778 selectively kills BRCA2-deficient cells and potentiates
the activity of PARPi niraparib in vivo to induce
tumor stasis in a BRCA2 KO DLD-1 mouse xenograft.
Furthermore, we illustrate how development of this approach has the
potential for addressing nucleases as a target class.