4OQB
Structure of Human PARP-1 bound to a DNA double strand break in complex with (2Z)-2-{4-[2-(morpholin-4-yl)ethoxy]benzylidene}-3-oxo-2,3-dihydro-1-benzofuran-7-carboxamide
Summary for 4OQB
Entry DOI | 10.2210/pdb4oqb/pdb |
Related | 4DQY 4OPX 4OQA |
Descriptor | Poly [ADP-ribose] polymerase 1, DNA (26-MER), ZINC ION, ... (5 entities in total) |
Functional Keywords | zinc finger, dna binding, parp, polymerase, dna repair, poly(adp-ribosyl)ation, transferase-dna-transferase inhibitor complex, transferase/dna/transferase inhibitor |
Biological source | Homo sapiens (human) More |
Cellular location | Nucleus : P09874 P09874 |
Total number of polymer chains | 6 |
Total formula weight | 191746.46 |
Authors | Pascal, J.M.,Steffen, J.D. (deposition date: 2014-02-07, release date: 2014-07-02, Last modification date: 2023-09-20) |
Primary citation | Patel, M.R.,Bhatt, A.,Steffen, J.D.,Chergui, A.,Murai, J.,Pommier, Y.,Pascal, J.M.,Trombetta, L.D.,Fronczek, F.R.,Talele, T.T. Discovery and Structure-Activity Relationship of Novel 2,3-Dihydrobenzofuran-7-carboxamide and 2,3-Dihydrobenzofuran-3(2H)-one-7-carboxamide Derivatives as Poly(ADP-ribose)polymerase-1 Inhibitors. J.Med.Chem., 57:5579-5601, 2014 Cited by PubMed Abstract: Novel substituted 2,3-dihydrobenzofuran-7-carboxamide (DHBF-7-carboxamide) and 2,3-dihydrobenzofuran-3(2H)-one-7-carboxamide (DHBF-3-one-7-carboxamide) derivatives were synthesized and evaluated as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). A structure-based design strategy resulted in lead compound 3 (DHBF-7-carboxamide; IC50 = 9.45 μM). To facilitate synthetically feasible derivatives, an alternative core was designed, DHBF-3-one-7-carboxamide (36, IC50 = 16.2 μM). The electrophilic 2-position of this scaffold was accessible for extended modifications. Substituted benzylidene derivatives at the 2-position were found to be the most potent, with 3',4'-dihydroxybenzylidene 58 (IC50 = 0.531 μM) showing a 30-fold improvement in potency. Various heterocycles attached at the 4'-hydroxyl/4'-amino of the benzylidene moiety resulted in significant improvement in inhibition of PARP-1 activity (e.g., compounds 66-68, 70, 72, and 73; IC50 values from 0.718 to 0.079 μM). Compound 66 showed selective cytotoxicity in BRCA2-deficient DT40 cells. Crystal structures of three inhibitors (compounds (-)-13c, 59, and 65) bound to a multidomain PARP-1 structure were obtained, providing insights into further development of these inhibitors. PubMed: 24922587DOI: 10.1021/jm5002502 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (3.362 Å) |
Structure validation
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