Abstract 5495: PHI-501, a potent and novel inhibitor of NRAS mutated acute myeloid leukemia

Purpose: Development of the first-in-class inhibitor of NRAS mutated acute myeloid leukemia. PHI-501 has potent activity against receptor tyrosine kinases and intracellular kinases related to STAT, AKT, and ERK signaling. Description: Preclinical testing of PHI-501 for efficacy against NRAS mutations both in vitro and in vivo xenografts. Summary: Mutations in the RAS genes (including KRAS, NRAS, and HRAS) are discovered in about 30% of all tumors. KRAS is the most frequently mutated gene in cancers found in pancreatic, colon, and lung, while NRAS mutations around the hot spots at codons 12, 13, and 61 are more common in AML (10.3%). PHI-501 is a novel small molecule inhibitor intended for the treatment of AML in patients expressing the N-RAS activating mutation. PHI-501 presented higher selectivity within a panel of 355 protein kinases. PHI-501 exerts their anti-proliferative effects by inducing apoptosis and G0-G1 arrest and significantly induce apoptotic markers (cleaved PARP and caspase 3) in both Ba/F3-NRAS-G12D and OCI-AML3 cells. The results of Western blot analysis showed that PHI-501 attenuate phosphorylation of p70S6K1, AKT, and p38 in OCI-AML3 After 21 days of the treatment in subcutaneous OCI-AML3 human AML xenograft model, PHI-501 showed significant inhibition of tumor growth (TGI) in a dose-dependent manner. Compared to the vehicle group, the 40 mg/kg group demonstrated a 74.0% lower average tumor volume (P