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. 2019 Jun 13;62(11):5330-5357. doi: 10.1021/acs.jmedchem.8b01709.
Uday Kiran Velagapudi  1 ,  Marie-France Langelier  2 ,  Cristina Delgado-Martin  3 ,  Morgan E Diolaiti  3 ,  Sietske Bakker  3 ,  Alan Ashworth  3  4 ,  Bhargav A Patel  1 ,  Xuwei Shao  1 ,  John M Pascal  2 ,  Tanaji T Talele  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
  • 2. Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Quebec H3T 1J4 , Canada.
  • 3. UCSF Helen Diller Family Comprehensive Cancer Center , University of California , San Francisco , California 94158 , United States.
  • 4. Department of Medicine , University of California , San Francisco , California 94158 , United States.
PMID: 31042381 DOI: 10.1021/acs.jmedchem.8b01709
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 IC50 = 434 nM) led to a tetrazolyl analogue (51, IC50 = 35 nM) with improved inhibition. Isosteric replacement of the tetrazole ring with a carboxyl group (60, IC50 = 68 nM) gave a promising new lead, which was subsequently optimized to obtain analogues with potent PARP-1 IC50 values (4-197 nM). PARP enzyme profiling revealed that the majority of compounds are selective toward PARP-2 with IC50 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 (IC50 = 30 nM/2 nM) inhibitor, demonstrated selective cytotoxic effect toward breast Cancer gene 1 ( BRCA1)-deficient cells compared to isogenic BRCA1-proficient cells.