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

Publication ,  Journal Article
Min, J; Guo, K; Suryadevara, PK; Zhu, F; Holbrook, G; Chen, Y; Feau, C; Young, BM; Lemoff, A; Connelly, MC; Kastan, MB; Guy, RK
Published in: J Med Chem
January 28, 2016

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.

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Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

January 28, 2016

Volume

59

Issue

2

Start / End Page

559 / 577

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Structure-Activity Relationship
  • Radiation-Sensitizing Agents
  • Quinazolines
  • Microsomes, Liver
  • Mice, Inbred C57BL
  • Mice
  • Medicinal & Biomolecular Chemistry
  • MCF-7 Cells
  • In Vitro Techniques
 

Citation

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Min, J., Guo, K., Suryadevara, P. K., Zhu, F., Holbrook, G., Chen, Y., … Guy, R. K. (2016). Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents. J Med Chem, 59(2), 559–577. https://doi.org/10.1021/acs.jmedchem.5b01092
Min, Jaeki, Kexiao Guo, Praveen K. Suryadevara, Fangyi Zhu, Gloria Holbrook, Yizhe Chen, Clementine Feau, et al. “Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.J Med Chem 59, no. 2 (January 28, 2016): 559–77. https://doi.org/10.1021/acs.jmedchem.5b01092.
Min J, Guo K, Suryadevara PK, Zhu F, Holbrook G, Chen Y, et al. Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents. J Med Chem. 2016 Jan 28;59(2):559–77.
Min, Jaeki, et al. “Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.J Med Chem, vol. 59, no. 2, Jan. 2016, pp. 559–77. Pubmed, doi:10.1021/acs.jmedchem.5b01092.
Min J, Guo K, Suryadevara PK, Zhu F, Holbrook G, Chen Y, Feau C, Young BM, Lemoff A, Connelly MC, Kastan MB, Guy RK. Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents. J Med Chem. 2016 Jan 28;59(2):559–577.
Journal cover image

Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

January 28, 2016

Volume

59

Issue

2

Start / End Page

559 / 577

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Structure-Activity Relationship
  • Radiation-Sensitizing Agents
  • Quinazolines
  • Microsomes, Liver
  • Mice, Inbred C57BL
  • Mice
  • Medicinal & Biomolecular Chemistry
  • MCF-7 Cells
  • In Vitro Techniques