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

Abstract 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<0.0001) and a 78.5% lower average tumor weight (P=0.0041). No significant body weight changes were observed in any of the groups. In toxicology and pharmacokinetic study, PHI-501 exhibited pharmacokinetic profiles favorable for oral administration in rodent, dog, and monkey and displayed acceptable in vivo and in vitro safety profiles. These results show the significant ability of PHI-501 to inhibit the progression of NRAS activated AML tumor growth, making it a strong candidate for the treatment of AML. Conclusion: The preclinical evaluation of PHI-501, a novel N-RAS inhibitor, showed clear evidence of anticancer activity for AML and improved efficacy in both in vitro and in vivo models. Consequently, PHI-501 is a new potent multi-kinase inhibitor with characteristics that warrant entry into human trials for the treatment of AML in patients expressing the N-RAS activating mutation. Citation Format: Ky-Youb Nam, Jung Hee Park, Kyung Ah Kim, Inje Shin, June H-J Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Hanna Cho, Seung-Hye Choi, Sandip Sengupta, Taebo Sim. PHI-501, a potent and novel inhibitor of NRAS mutated acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5495.