Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents

Jaeki Min, Kexiao Guo, Praveen K. Suryadevara, Fangyi Zhu, Gloria Holbrook, Yizhe Chen, Clementine Feau, Brandon M. Young, Andrew Lemoff, Michele C. Connelly, Michael B. Kastan, R. Kiplin Guy

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

We previously reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM) kinase, which is a target for novel radiosensitizing drugs. While our initial lead, compound 4, was relatively potent and nontoxic, it exhibited poor stability to oxidative metabolism and relatively poor selectivity against other kinases. The current study focused on balancing potency and selectivity with metabolic stability through structural modification to the metabolized site on the quinazoline core. We performed extensive structure-activity and structure-property relationship studies on this quinazoline ATM kinase inhibitor in order to identify structural variants with enhanced selectivity and metabolic stability. We show that, while the C-7-methoxy group is essential for potency, replacing the C-6-methoxy group considerably improves metabolic stability without affecting potency. Promising analogues 20, 27g, and 27n were selected based on in vitro pharmacology and evaluated in murine pharmacokinetic and tolerability studies. Compound 27g possessed significantly improve pharmacokinetics relative to that of 4. Compound 27g was also significantly more selective against other kinases than 4. Therefore, 27g is a good candidate for further development as a potential radiosensitizer.

Original languageEnglish (US)
Pages (from-to)559-577
Number of pages19
JournalJournal of Medicinal Chemistry
Volume59
Issue number2
DOIs
StatePublished - Jan 28 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

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    Min, J., Guo, K., Suryadevara, P. K., Zhu, F., Holbrook, G., Chen, Y., Feau, C., Young, B. M., Lemoff, A., Connelly, M. C., Kastan, M. B., & Guy, R. K. (2016). Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents. Journal of Medicinal Chemistry, 59(2), 559-577. https://doi.org/10.1021/acs.jmedchem.5b01092