Discovery of dual inhibitors of pan‐RAF and VEGFR2

Abstract Colorectal cancer is among the most common and lethal malignancies globally, with K‐Ras mutations found in about 45% of colorectal cancer patients. Early‐stage BRAF‐specific inhibitors have been developed to prevent aberrant activation of RAS/RAF/MEK/ERK signaling caused by K‐Ras mutation, however, these BRAF‐specific inhibitors lead to RAF dimer formation and paradoxical CRAF activation. Consequently, there is a need to develop pan‐RAF inhibitors. In addition, it was reported that the inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) is crucial for the treatment of colorectal cancer. In this study, we designed and synthesized 94 N ‐(phenyl)‐3‐(9 H ‐purin‐6‐yl)pyridine‐2‐amine derivatives, and discovered that N ‐(5‐(3‐(9 H ‐purin‐6‐yl)pyridin‐2‐ylamino)‐2‐fluorophenyl)‐3‐(trifluoromethyl)benzamide ( 15h ), 3‐(2‐cyanopropan‐2‐yl)benzamide derivative 16h , and 3,5‐bis(trifluoromethyl) benzamide derivative 17ab are the most potent dual inhibitors against LS513 (GI 50 = 0.08, 0.2, and 0.3 μM, respectively) and VEGFR2 (IC 50 = 0.01, 0.004, and 0.01 μM, respectively). These compounds are excellent preclinical candidates for the treatment of K‐Ras mutated colorectal cancer.