Affiliation:
1. Department of Chemistry, and Research Institute of Basic Science Incheon National University Incheon Republic of Korea
2. Institute for New Drug Development, Division of Life Sciences Incheon National University Incheon Republic of Korea
3. ILDONG Pharmaceutical Co. Ltd. Hwaseong Republic of Korea
4. Division of New Drug Development Autophagy Sciences Seoul Republic of Korea
5. Samjin Pharm. Co. Ltd. Seoul Republic of Korea
Abstract
AbstractColorectal 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‐(9H‐purin‐6‐yl)pyridine‐2‐amine derivatives, and discovered that N‐(5‐(3‐(9H‐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 (GI50 = 0.08, 0.2, and 0.3 μM, respectively) and VEGFR2 (IC50 = 0.01, 0.004, and 0.01 μM, respectively). These compounds are excellent preclinical candidates for the treatment of K‐Ras mutated colorectal cancer.
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