9RCI
Crystal Structure of Flap Endonuclease FEN1 with Compound 28
This is a non-PDB format compatible entry.
Summary for 9RCI
| Entry DOI | 10.2210/pdb9rci/pdb |
| Descriptor | Flap endonuclease 1, MAGNESIUM ION, 1,2-ETHANEDIOL, ... (5 entities in total) |
| Functional Keywords | endonuclease, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 78349.01 |
| Authors | Toste Rego, A.,Pica, A.,Cornaciu, I.,Burgdorf, L.,Mann, S.E. (deposition date: 2025-05-29, 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 Cited by 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: 40963090DOI: 10.1021/acs.jmedchem.5c01526 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.662 Å) |
Structure validation
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