title: Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents.
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.
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke University School of Medicine , 422 Seeley Mudd Building, Durham, North Carolina 27710, United States.
authors.forename: Kexiao
authors.initials: K
authors.lastname: Guo
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Suryadevara
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: Gloria
authors.initials: G
authors.lastname: Holbrook
authors.forename: Yizhe
authors.initials: Y
authors.lastname: Chen
authors.forename: Clementine
authors.initials: C
authors.lastname: Feau
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Young
authors.forename: Andrew
authors.initials: A
authors.lastname: Lemoff
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke University School of Medicine , 422 Seeley Mudd Building, Durham, North Carolina 27710, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors*; D003114:Colony-Forming Units Assay; D016503:Drug Delivery Systems; D015195:Drug Design; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins