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

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-Ras^G12D) 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.