9RDI

Crystal Structure of Flap Endonuclease FEN1 with Compound 5

This is a non-PDB format compatible entry.

Summary for 9RDI

• Entry DOI: 10.2210/pdb9rdi/pdb
• Related: 9RCI
• Descriptor: Flap endonuclease 1, 2-methyl-9-oxidanyl-6-(phenylmethyl)-3,4-dihydropyrazino[1,2-c]pyrimidine-1,8-dione, 6-tungstotellurate(VI), ... (5 entities in total)
• Functional Keywords: endonuclease, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 92484.22

Authors

Toste Rego, A.,Pica, A.,Cornaciu, I.,Burgdorf, L.,Mann, S.E. (deposition date: 2025-06-02, release date: 2025-09-24, Last modification date: 2025-10-22)

Primary citation

Mann, S.E.,Lefranc, J.,Alkhatib, O.,Boivin, R.,Bomke, J.,Byrne, R.T.,Cassona, C.P.,Chen, X.,Cornaciu, I.,Costales, P.,Davis, O.A.,DeSelm, L.,Elinati, E.,Follows, B.,Galbiati, A.,Goldner, C.,Hayre, J.K.,Jorand-Lebrun, C.,Lademann, C.A.,Leuthner, B.,Majithiya, J.B.,Malta, C.F.,Mason, B.,McWhirter, C.L.,Neff, B.,Nissink, J.W.M.,Pehl, U.,Petersson, C.,Pica, A.,Pinto, M.F.,Rajendra, E.,Rakers, C.,Toste Rego, A.,Robinson, H.M.R.,Sala-Hojman, A.,Schaedler, T.A.,Schurmann, P.J.L.,Silva, D.O.,Smith, G.C.M.,Sorrell, F.,Webster, G.R.,Zenke, F.T.,Heald, R.A.,Burgdorf, L.T.
Fragment-Based Discovery and Structure-Led Optimization of MSC778, the First Potent, Selective, and Orally Bioavailable FEN1 Inhibitor.
J.Med.Chem., 68:20410-20434, 2025

PubMed 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 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 , the first potent, selective, and orally bioavailable FEN1 inhibitor. We describe our metal-chelating fragment screening approach and structure-based optimization to identify , using structural insights to drive design. Consistent with FEN1 inhibition, selectively kills -deficient cells and potentiates the activity of PARPi niraparib to induce tumor stasis in a KO DLD-1 mouse xenograft. Furthermore, we illustrate how development of this approach has the potential for addressing nucleases as a target class.

PubMed: 40963090
DOI: 10.1021/acs.jmedchem.5c01526

Experimental method

X-RAY DIFFRACTION (2.105 Å)