Improvement of the metabolic stability of pan‐RAF/VEGFR2 dual inhibitors

Abstract

Development of dual inhibitors of pan‐RAF/VEGFR2 is important for the treatment of K‐Ras mutated colorectal cancer, which is one of the most common and lethal malignancies. Building upon our studies in dual inhibitors of pan‐RAF/VEGFR2, we designed and synthesized new dual inhibitor candidates by installing a urea or guanidine moiety to the previously reported dual inhibitors in order to enhance both metabolic stability and solubility. Various 1‐(5‐((3‐(9H‐purin‐6‐yl)pyridin‐2‐yl)amino)‐2‐fluorophenyl)‐3‐phenylurea and 1‐(5‐((3‐(9H‐purin‐6‐yl)pyridin‐2‐yl)amino)‐2‐fluorophenyl)‐3‐phenylguanidine derivatives were synthesized, and their antiproliferative activities against LS513 cell (K‐RasG12D) and VEGFR2 were evaluated. Among the tested compounds, 1‐(5‐((3‐(9H‐purin‐6‐yl)pyridin‐2‐yl)amino)‐2‐fluorophenyl)‐3‐(3‐fluorophenyl)urea (7b) and 1‐(5‐((3‐(9H‐purin‐6‐yl)pyridin‐2‐yl)amino)‐2‐fluorophenyl)‐3‐(4‐chloro‐3‐trifluoromethyl)phenyl)urea (7e) are the most potent dual inhibitors against LS513 (GI50 = 0.1 and 0.06 μM, respectively) and VEGFR2 (IC50 = 0.03 and 0.06 μM, respectively). The preclinical study with these compounds are currently underway.