Discovery of potent Pan-Raf inhibitors with increased solubility to overcome drug resistance

Abstract Despite various applications of kinase inhibitors in oncology and inflammatory diseases, the emergence of resistance still remains the major barrier to achieve long-term remission in cancer treatment. With the aim of overcoming the resistance induced by type IIB BRaf V600E selective inhibitor vemurafenib, and further ameliorating the antiproliferative activity, a novel type IIA Pan-Raf inhibitors Ia – Io based on pyrrolo[2,3- d ] pyrimidine scaffold were designed and evaluated in this work. Herein, we tried to improve the cellular potency of the target compounds by increasing their solubility. Among them, Il , with the solubility of 0.107 mg/mL, demonstrated favorable cellular activity against vemurafenib-resistant carcinoma cells including BRaf WT phenotypic melanoma SK-MEL-2 and BRaf V600E phenotypic colorectal cancer HT-29 cell lines. Based on the well solubility, Il exhibited good metabolic stability compared to sorafenib and showed favorable pharmacokinetic profiles in rats. As for the biological mechanism research, Il had the similar P-ERK kinase inhibitory activity in A375 and SK-Mel-2 cells as our previously lead P-2 . Il may become a good candidate compound to overcome the resistance associated with vemurafenib.