RAS Inhibitors

The second platform in the PHusis pipeline targets the regulation of mutated KRAS, one of the most critical unmet needs in cancer therapy today. The high frequency of KRAS mutations in some human cancers, principally colorectal, lung and pancreatic cancer, and overall ~25% of all human cancers, has stimulated intense interest in the development of anti-RAs inhibitors for cancer therapy but to date has produced no drug candidates.

CNKSR1
PHusis has taken an approach to identify small molecules that will inhibit the signaling activity and growth of mutant KRAS but not non-mutated KRAS cells, and has identified nanomolar PH-domain inhibitors of the essential mutant-KRAS regulatory protein CNKSR1. CNKSR1 has been shown to be a critical protein anchoring mutant KRAS in its plasma membrane signaling nanocluster allowing its activation and downstream signaling.

Inhibitors have been identified with selective growth inhibitory effects in mutant KRAS cell lines but not in non-mutant KRAS lines. The pattern of activity of the inhibitors mimics the use of molecular inhibition of CNKSR1 and KRAS. Initial leads have shown antitumor activity in animal models.

Lead optimization and pre-clinical development is ongoing, leading to a Phase 1 trial in the next 15 months.

PLEK
The PH-domain of PLEK has also been identified as critical for the activation of mutant KRAS. PHusis has resolved crystal structure of the PLEK PH domain and has begun a screening discovery program against this novel drug target. Lead selection is anticipated in the next 12 months.