Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1

Trilles, Richard; Beglov, Dmitri; Chen, Qiujia; He, Hongzhen; Wireman, Randall; Reed, April; Chennamadhavuni, Spandan; Panek, James S.; Brown, Lauren E.; Vajda, Sandor; Porco, John A.; Kelley, Mark R.; Georgiadis, Millie M.

doi:10.1021/acs.jmedchem.8b01529

Title: Discovery of Macrocyclic Inhibitors of Apurinic/Apyrimidinic Endonuclease 1

Journal Article · Thu Jan 17 00:00:00 EST 2019 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b01529· OSTI ID:1502255

Trilles, Richard ^[1]; Beglov, Dmitri ^[2]; Chen, Qiujia ^[3]; He, Hongzhen ^[3]; Wireman, Randall ^[4]; Reed, April ^[4]; Chennamadhavuni, Spandan ^[5]; Panek, James S. ^[1];

^[1];

^[2];

^[1]; Kelley, Mark R. ^[4];

^[6]

Boston Univ., MA (United States). Center for Molecular Discovery (BU-CMD)
Boston Univ., MA (United States)
Indiana Univ., Indianapolis, IN (United States). School of Medicine
Indiana Univ., Indianapolis, IN (United States). School of Medicine, Herman B. Wells Center for Pediatric Research
Boston Univ., MA (United States). Center for Molecular Discovery (BU-CMD); Emory Univ., Atlanta, GA (United States)
Indiana Univ., Indianapolis, IN (United States). School of Medicine; Purdue Univ., Indianapolis, IN (United States). Purdue School of Science

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. Here in this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children’s Foundation; Riley Children’s Foundation; USDOE

Grant/Contract Number:: R01CA205166; R01CA167291; R24 GM111625; R35 GM118078

OSTI ID:: 1502255

Journal Information:: Journal of Medicinal Chemistry, Vol. 62, Issue 4; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 9 works

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