Pan-RAF Inhibitor (JZP815)

Pan-Raf inhibitor programme: Overcoming drug resistance mechanisms

The pan-RAF inhibitor programme aims to overcome resistance mechanisms associated with clinically approved B-RAF selective drugs.

Mutations leading to uncontrolled signalling via the RAS-RAF-MAPK pathway are seen in over one third of all cancers. The RAF kinases (A-RAF, B-RAF and C-RAF) are an integral part of this pathway, with B-RAF mutations commonly seen in the clinic. Although most B-RAFV600E/K mutant skin cancers are initially sensitive to approved B-RAF selective drugs, treatment resistance often leads to disease progression. Moreover, B-RAFV600E mutant colorectal cancers are surprisingly insensitive to these B-RAF selective agents due to the functions of other RAF family members. Importantly, B-RAF selective therapies fail to show clinical benefit against the more prevalent RAS-mutated tumours.

To overcome these resistance mechanisms our scientists developed a pan-RAF inhibitor programme. The lead chemical series demonstrated monotherapy in vivo efficacy in a B-RAFV600E mutant colorectal cancer xenograft model, where approved B-RAF selective drugs are ineffective as monotherapy. In addition, this series shows monotherapy in vivo efficacy in a RAS-mutant colorectal cancer xenograft model.