Abstract
Deregulation of the receptor tyrosine kinase RET has been implicated in medullary thyroid cancer, a small percentage of lung adenocarcinomas, endocrine-resistant breast cancer and pancreatic cancer. There are several clinically approved multi-kinase inhibitors that target RET as a secondary pharmacology but additional activities, most notably inhibition of KDR, lead to dose-limiting toxicities. There is, therefore, a clinical need for more specific RET kinase inhibitors. Herein we report our efforts towards identifying a potent and selective RET inhibitor using vandetanib 1 as the starting point for structure-based drug design. Phenolic anilinoquinazolines exemplified by 6 showed improved affinities towards RET but, unsurprisingly, suffered from high metabolic clearance. Efforts to mitigate the metabolic liability of the phenol led to the discovery that a flanking substituent not only improved the hepatocyte stability, but could also impart a significant gain in selectivity. This culminated in the identification of 36; a potent RET inhibitor with much improved selectivity against KDR.
Highlights
RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that is required for normal development, maturation and maintenance of several tissues and cell types [1]
The small molecule inhibitors vandetanib 1 and cabozantinib 2 (Fig. 1) exemplify this approach. Both have been approved for the treatment of advanced metastatic medullary thyroid cancer (MTC) [2,3] and are undergoing Phase II trials in lung adenocarcinoma (LAD) [4,5], RET inhibition is a secondary pharmacology of these drugs, which were initially developed as inhibitors of other receptor tyrosine kinases
Our initial aim was to prepare to number of anilinoquinazolines to explore the affinity and selectivity towards RET as compared to 1 [11,12]
Summary
RET (REarranged during Transfection) is a receptor tyrosine kinase (RTK) that is required for normal development, maturation and maintenance of several tissues and cell types [1]. The small molecule inhibitors vandetanib 1 and cabozantinib 2 (Fig. 1) exemplify this approach Both have been approved for the treatment of advanced metastatic MTC [2,3] and are undergoing Phase II trials in LAD [4,5], RET inhibition is a secondary pharmacology of these drugs, which were initially developed as inhibitors of other receptor tyrosine kinases. Both agents target KDR (VEGFR2), whilst 1 has additional activity versus EGFR and 2 versus MET. Given that the 6 and 7 positions on the quinazoline ring point primarily towards solvent, we expected these substituents to have a less pronounced role on selectivity, and fixed both positions as methoxy groups for the initial round of optimization
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