ORIC-613

In cell viability assays, selective PLK4 inhibitors were potent in the parental G95 cells and lost activity in L95 cells, unlike less selective inhibitors whose potency did not depend on PLK4. Oral dosing of a selective PLK4 inhibitor resulted in tumor growth inhibition in TRIM37 high xenograft tumors with no body weight loss.In summary, we have discovered that highly selective small molecule inhibitors of PLK4 confirm the potential of the synthetic lethal impact in treating tumors with high levels of TRIM37.

Importantly, cell potency in TRIM37 high cancer cells was rescued with knockdown of TRIM37, illustrating that selective PLK4 inhibitors are synthetic lethal with TRIM37 amplification. Oral administration of ORIC PLK4 inhibitors resulted in regressions of TRIM37 high xenograft tumors, with corresponding PD effects and no body weight loss.In summary, we have discovered novel, potent, highly selective small molecule inhibitors of PLK4 that are orally bioavailable and confirmed the potential for this new target in treating tumors with high levels of TRIM37.