Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAFV600E mutant cancer

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Abstract

Aims:

BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF-mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6 months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan-RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations.

Main methods:

Using a structure-based molecular modeling, we discovered INU-152, which is a potent and selective pan-RAF inhibitor. In kinase assays against RAF proteins, INU-152 exhibited a potent effect against RAF isoforms. INU-152 was tested for its inhibitory effect on the growth of human cancer cells bearing BRAFV600E. To study in vivo effects, INU-152 was administered using human melanoma and colorectal cancer xenograft models. To explore INU-152′s potential as a prospective drug candidate, pharmacokinetic studies and toxicity tests were performed using mice.

Key findings:

To inhibit and suppress paradoxical activation in mutant RAS cancer cells completely, it is important for RAF inhibitors to exhibit potent inhibitory activities against RAF isoforms.

Significance:

INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations.

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