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Barsanti PA, Aversa RJ, Jin X, et al. Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors. ACS Med Chem Lett. 2014;6(1):37-41doi: 10.1021/ml500353p.
Barsanti, P. A., Aversa, R. J., Jin, X., Pan, Y., Lu, Y., Elling, R., Jain, R., Knapp, M., Lan, J., Lin, X., Rudewicz, P., Sim, J., Taricani, L., Thomas, G., Xiao, L., & Yue, Q. (2015). Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors. ACS medicinal chemistry letters, 6(1), 37-41. https://doi.org/10.1021/ml500353p
Barsanti, Paul A, et al. "Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors." ACS medicinal chemistry letters vol. 6,1 (2015): 37-41. doi: https://doi.org/10.1021/ml500353p
Barsanti PA, Aversa RJ, Jin X, Pan Y, Lu Y, Elling R, Jain R, Knapp M, Lan J, Lin X, Rudewicz P, Sim J, Taricani L, Thomas G, Xiao L, Yue Q. Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors. ACS Med Chem Lett. 2014 Nov 20;6(1):37-41. doi: 10.1021/ml500353p. eCollection 2015 Jan 08. PMID: 25589927; PMCID: PMC4291715.
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ACS Med Chem Lett. 2014 Nov 20;6(1):37-41. doi: 10.1021/ml500353p. eCollection 2015 Jan 08.

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

ACS medicinal chemistry letters

Paul A Barsanti, Robert J Aversa, Xianming Jin, Yue Pan, Yipin Lu, Robert Elling, Rama Jain, Mark Knapp, Jiong Lan, Xiaodong Lin, Patrick Rudewicz, Janet Sim, Lorena Taricani, George Thomas, Linda Xiao, Qin Yue

Affiliations

  1. Global Discovery Chemistry Oncology, Novartis Institutes for Biomedical Research , 5300 Chiron Way, Emeryville, California 94608, United States.

PMID: 25589927 PMCID: PMC4291715 DOI: 10.1021/ml500353p

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.

Keywords: ATR; CYP3A4 TDI; Fsp3; deuterium; structure-based drug design

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