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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 06 13; 62(11):5330-5357.JM

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.

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Authors+Show Affiliations

Velagapudi UK
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
Langelier MF
Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Quebec H3T 1J4 , Canada.
Delgado-Martin C
UCSF Helen Diller Family Comprehensive Cancer Center , University of California , San Francisco , California 94158 , United States.
Diolaiti ME
UCSF Helen Diller Family Comprehensive Cancer Center , University of California , San Francisco , California 94158 , United States.
Bakker S
UCSF Helen Diller Family Comprehensive Cancer Center , University of California , San Francisco , California 94158 , United States.
Ashworth A
UCSF Helen Diller Family Comprehensive Cancer Center , University of California , San Francisco , California 94158 , United States. Department of Medicine , University of California , San Francisco , California 94158 , United States.
Patel BA
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
Shao X
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.
Pascal JM
Department of Biochemistry and Molecular Medicine , Université de Montréal , Montréal , Quebec H3T 1J4 , Canada.
Talele TT
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences , St. John's University , Queens , New York 11439 , United States.

MeSH

AdenosineAmino Acid MotifsBenzofuransBiocatalysisCell Line, TumorChemistry Techniques, SyntheticDrug DesignHumansInhibitory Concentration 50Models, MolecularPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31042381

Citation

Velagapudi, Uday Kiran, et al. "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." Journal of Medicinal Chemistry, vol. 62, no. 11, 2019, pp. 5330-5357.
Velagapudi UK, Langelier MF, Delgado-Martin C, et al. 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;62(11):5330-5357.
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. (2019). 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. Journal of Medicinal Chemistry, 62(11), 5330-5357. https://doi.org/10.1021/acs.jmedchem.8b01709
Velagapudi UK, et al. 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 06 13;62(11):5330-5357. PubMed PMID: 31042381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Velagapudi,Uday Kiran, AU - Langelier,Marie-France, AU - Delgado-Martin,Cristina, AU - Diolaiti,Morgan E, AU - Bakker,Sietske, AU - Ashworth,Alan, AU - Patel,Bhargav A, AU - Shao,Xuwei, AU - Pascal,John M, AU - Talele,Tanaji T, Y1 - 2019/05/24/ PY - 2019/5/3/pubmed PY - 2020/6/17/medline PY - 2019/5/3/entrez SP - 5330 EP - 5357 JF - Journal of medicinal chemistry JO - J Med Chem VL - 62 IS - 11 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/31042381/Design_and_Synthesis_of_Poly_ADP_ribose__Polymerase_Inhibitors:_Impact_of_Adenosine_Pocket_Binding_Motif_Appendage_to_the_3_Oxo_23_dihydrobenzofuran_7_carboxamide_on_Potency_and_Selectivity_ DB - PRIME DP - Unbound Medicine ER -