Uday Kiran Velagapudi1, Marie-France Langelier2, Cristina Delgado-Martin3, Morgan E Diolaiti3, Sietske Bakker3, Alan Ashworth3,4, Bhargav A Patel1, Xuwei Shao1, John M Pascal2, Tanaji T Talele1. 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.
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.
Poly(adenosine 5'-diphosphate-ribose) polymerase (n class="Gene">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-1adenosine-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.
Authors: Tom E H Ogden; Ji-Chun Yang; Marianne Schimpl; Laura E Easton; Elizabeth Underwood; Philip B Rawlins; Michael M McCauley; Marie-France Langelier; John M Pascal; Kevin J Embrey; David Neuhaus Journal: Nucleic Acids Res Date: 2021-02-26 Impact factor: 16.971
Authors: Yasmin M Syam; Manal M Anwar; Somaia S Abd El-Karim; Khaled M Elokely; Sameh H Abdelwahed Journal: Molecules Date: 2022-08-02 Impact factor: 4.927