6NRF

Crystal Structure of human PARP-1 ART domain bound to inhibitor UTT103

Summary for 6NRF

• Entry DOI: 10.2210/pdb6nrf/pdb
• Descriptor: Poly [ADP-ribose] polymerase 1, CITRIC ACID, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: parp-1, poly(adp-ribose) polymerase, parp inhibitor, parp1, artd1, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 30839.97

Authors

Langelier, M.F.,Pascal, J.M. (deposition date: 2019-01-23, release date: 2019-08-14, Last modification date: 2024-11-06)

Primary citation

Velagapudi, U.K.,Langelier, M.F.,Delgado-Martin, C.,Diolaiti, M.E.,Bakker, S.,Ashworth, A.,Patel, B.A.,Shao, X.,Pascal, J.M.,Talele, T.T.
Design and Synthesis of Poly(ADP-ribose) Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity.
J.Med.Chem., 62:5330-5357, 2019

PubMed Abstract: Poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors are a class of anticancer drugs that block the catalytic activity of PARP proteins. Optimization of our lead compound 1 (( Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide; PARP-1 IC = 434 nM) led to a tetrazolyl analogue (51, IC = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC values comparable to clinical inhibitors. X-ray crystal structures of the key inhibitors bound to PARP-1 illustrated the mode of interaction with analogue appendages extending toward the PARP-1 adenosine-binding pocket. Compound 81, an isoform-selective PARP-1/-2 (IC = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.

PubMed: 31042381
DOI: 10.1021/acs.jmedchem.8b01709

Experimental method

X-RAY DIFFRACTION (2 Å)