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Title: Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors

Abstract

A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1405002
Resource Type:
Journal Article
Resource Relation:
Journal Name: ACS Medicinal Chemistry Letters; Journal Volume: 6; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Barsanti, Paul A., Aversa, Robert J., Jin, Xianming, Pan, Yue, Lu, Yipin, Elling, Robert, Jain, Rama, Knapp, Mark, Lan, Jiong, Lin, Xiaodong, Rudewicz, Patrick, Sim, Janet, Taricani, Lorena, Thomas, George, Xiao, Linda, and Yue, Qin. Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors. United States: N. p., 2015. Web. doi:10.1021/ml500353p.
Barsanti, Paul A., Aversa, Robert J., Jin, Xianming, Pan, Yue, Lu, Yipin, Elling, Robert, Jain, Rama, Knapp, Mark, Lan, Jiong, Lin, Xiaodong, Rudewicz, Patrick, Sim, Janet, Taricani, Lorena, Thomas, George, Xiao, Linda, & Yue, Qin. Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors. United States. doi:10.1021/ml500353p.
Barsanti, Paul A., Aversa, Robert J., Jin, Xianming, Pan, Yue, Lu, Yipin, Elling, Robert, Jain, Rama, Knapp, Mark, Lan, Jiong, Lin, Xiaodong, Rudewicz, Patrick, Sim, Janet, Taricani, Lorena, Thomas, George, Xiao, Linda, and Yue, Qin. Thu . "Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors". United States. doi:10.1021/ml500353p.
@article{osti_1405002,
title = {Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors},
author = {Barsanti, Paul A. and Aversa, Robert J. and Jin, Xianming and Pan, Yue and Lu, Yipin and Elling, Robert and Jain, Rama and Knapp, Mark and Lan, Jiong and Lin, Xiaodong and Rudewicz, Patrick and Sim, Janet and Taricani, Lorena and Thomas, George and Xiao, Linda and Yue, Qin},
abstractNote = {A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.},
doi = {10.1021/ml500353p},
journal = {ACS Medicinal Chemistry Letters},
number = 1,
volume = 6,
place = {United States},
year = {Thu Jan 08 00:00:00 EST 2015},
month = {Thu Jan 08 00:00:00 EST 2015}
}