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

  • J Med Chem. 2025 Sep 17. doi: 10.1021/acs.jmedchem.5c01526.
Sam E Mann  1 ,  Julien Lefranc  2 ,  Omar Alkhatib  1 ,  Roch Boivin  3 ,  Jörg Bomke  2 ,  Robert T Byrne  4 ,  Carolina P Cassona  5 ,  Xiaoling Chen  3 ,  Irina Cornaciu  6 ,  Paula Costales  1 ,  Owen A Davis  1 ,  Lizbeth DeSelm  3 ,  Elias Elinati  1 ,  Bruce Follows  3 ,  Alessandro Galbiati  1 ,  Christoph Göldner  2 ,  Jasvinder K Hayre  1 ,  Catherine Jorand-Lebrun  3 ,  Claudio A Lademann  2 ,  Birgitta Leuthner  2 ,  Jayesh B Majithiya  1 ,  Catarina F Malta  5 ,  Bethany Mason  1 ,  Claire L McWhirter  1 ,  Bernd Neff  2 ,  J Willem M Nissink  1 ,  Ulrich Pehl  2 ,  Carl Petersson  2 ,  Andrea Pica  6 ,  Maria Filipa Pinto  1 ,  Eeson Rajendra  1 ,  Christin Rakers  2 ,  Ana Toste Rêgo  1 ,  Helen M R Robinson  1 ,  Ada Sala-Hojman  2 ,  Theresia A Schaedler  1 ,  Paul J L Schürmann  1 ,  Diana O Silva  5 ,  Graeme C M Smith  1 ,  Fiona Sorrell  2 ,  Gina R Webster  1 ,  Frank T Zenke  2 ,  Robert A Heald  1 ,  Lars T Burgdorf  2
Affiliations
  • 1. Artios Pharma Ltd., B940, Babraham Research Campus, Cambridge CB22 3FH, U.K.
  • 2. Merck Healthcare KGaA, Darmstadt 64293, Germany.
  • 3. EMD Serono Research & Development Institute, Billerica, Massachusetts 018-21-3936, United States.
  • 4. Crelux GmbH, Am Haag 16, Gräfelfing 82166, Germany.
  • 5. IBET Instituto de Biologia, Oeiras 2781-901, Portugal.
  • 6. ALPX, 71 Avenue des Martyrs, Grenoble 38000, France.
PMID: 40963090 DOI: 10.1021/acs.jmedchem.5c01526
Abstract

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.

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