Abstract 2461: Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance.

Although the ALK inhibitor crizotinib has clinical efficacy in selected ALK positive NSCLC patients, the majority of patients who initially respond eventually relapse. Several mechanisms of resistance have been proposed including amplification, resistance mutations, as well as alternative pathway drivers including EGFR, cKIT and IGF1R. We report here the discovery of a novel scaffold of ALK inhibitors and optimization effort that led to the discovery of AZD3463 a novel dual in vivo active ALK and IGF1R inhibitor. An in house subset screening of kinase inhibitors and de novo studies identified 4-(1H-indol-3-yl)pyrimidin-2-amine analogs as potent ALK inhibitors. Modeling studies were utilized to guide the SAR strategy around the aminopyrimidine group which afforded several lead compounds. Early SAR efforts quickly determined that smaller substituents, chloro and methyl, were optimal in the C5 position of the pyrimidine, and that aniline is preferred over several other amino heterocycles investigated. Parallel medicinal chemistry strategies were executed for the optimization of the aniline and indole. These studies suggested that a 2,4-substituted aniline provided optimal potency and selectivity in conjunction with a variety of heterocycles in C4 position of the pyrimdine. Cyclic amines in the C4 position of the aniline led to simultaneous improvement of potency and metabolic stability. The inhibition of IGF1R in vitro was maintained and modulation of glucose levels in vivo was observed with the optimized compounds and AZD3463. AZD3463 demonstrated superior potency to crizotinib in vivo (H3122 PD unbound EC50=0.16 nM). In summary, detailed SAR studies were executed on the 4-(1H-indol-3-yl)pyrimidin-2-amine template that produced potent inhibitors of ALK with improved physical chemical and ADME properties, and identified AZD3463, a novel equipotent ALK and IGF1R inhibitor, potent in ALK-driven preclinical models and in a variety of crizotinib-resistant models. We present herein the design and synthesis of AZD3463 as well as its overall properties. Citation Format: Jamal C. Saeh, Bin Yang, Tim Pontz, Kumar Thakur, Bo Peng, Lisa Drew, Caroline Rivard, Dan Widzowski, Jane Cheng, Douglas Ferguson, Brenda McDermott, Minhui Shen, John McNulty, Ryohei Katayama, Jeffrey Engleman, Alice Shaw, Daniel Russell, Graeme Smith. Design and synthesis of AZD3463, a novel orally bioavailable dual ALK and IGF1R inhibitor, inhibits growth of crizotinib resistance cell lines with multiple mechanisms of acquired resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2461. doi:10.1158/1538-7445.AM2013-2461