PHI-501

Regardless of the therapeutic effect of class I BRAF inhibitors such as vemurafenib, dabrafenib and encorafenib, melanoma patients with BRAF non-V600/RAS mutations remain limited response...The effect of PHI-501 on anchorage independent growth and cell proliferation compared to vemurafenib or belvarafenib (pan-RAF inhibitor) were tested in A375 (BRAFV600E), C8161 (BRAFG464E) and SK-MEL-2 (NRASQ61R) melanoma cell lines by soft agar assay, western blot and FACS analysis... PHI-501, a novel pan-RAF inhibitor, has potent oral anti-tumor activity. Melanoma cells harboring BRAF non-V600/NRAS or BRAF common V600E mutations exhibited significantly reduced proliferation, increased apoptosis and inhibited migration upon treatment with PHI-501. The results of this study suggest that PHI-501 has a potential to overcome the limited response in the treatment of melanoma, and warrant evaluation of PHI-501 as a single agent to treat both BRAF-and NRAS-mutated metastatic melanoma.

Long-term therapy with dabrafenib (BRAF inhibitor), cobimetinib or trametinib (MEK inhibitor) led to the establishment of the drug-resistant SK-MEL-3 (BRAF V600E) and SK-MEL-30 (NRAS Q61K) melanoma cell line. PHI-501 demonstrated potent growth inhibition (GI50 <1 µM) in seven melanoma cell lines harboring BRAF V600E or NRAS mutations. Melanoma cells resistant to RAF or MEK-targeted treatments or harboring NRAS mutation exhibited strong antiproliferative activity when treated with PHI-501, a highly potent pan-RAF/DDR dual inhibitor. The results of this study suggest that PHI-501, as a single agent, has the potential to overcome the restricted response in the treatment of melanoma.

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.