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 BRafWT phenotypic
melanoma SK-MEL-2 and BRafV600E 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.