In the current work, preclinical evaluation of two novel pan-RAF inhibitors (CTCKS15 and CTCKS16 were performed. CTCKS15 and CTCKS16 were preliminary evaluated for their selectivity over a panel of kinases and their binding mode to v600eBRAF were investigated by X-ray crystallography. The effect of CTCKS15 and CTCKS16 over different cancer subtypes were determined. <i>In vitro</i> anticancer activity was investigated over different melanoma cell lines. In addition, v600eBRAF resistant model was developed to test both compounds against resistant melanoma. <i>In-vivo</i> xerograph showed the ability of both compounds to reduce tumor size over 21 days of treatment. Our results showed the superiority of pan RAF inhibitors over selective v600eBRAF such as vemurafenib in treatment of both resistant and non-resistant melanomas. We anticipate our results will encourage the usage of pan RAF inhibitor as the first line for treatment of resistant melanoma and may replace combined therapy.

Discovery of pan RAF inhibitors CTCKS15 and CTCKS16 for treatment of resistant melanoma

ACS Fall 2020 Virtual Meeting

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