Repare Therapeutics Inc. disclosed polo-like kinase 4 (PLK4) as the target of its RP-1664 development program and reported comprehensive preclinical data for both RP-1664 and the Company?s Pol? inhibitor, RP-3467. RP-1664 is a potential first-in-class, selective, oral PLK4 inhibitor that is synthetic lethal with TRIM37 amplification or overexpression in solid tumors.

Tumors rely on PLK4 for survival in the presence of high levels of TRIM37. Preclinical studies demonstrate RP-1664 drives potent synthetic lethality in TRIM37-high tumor models, both in vitro and in vivo. Elevated TRIM37 is a feature found across a range of solid tumors and in nearly all high-grade neuroblastomas.

RP-3467 is a potential best-in-class inhibitor of DNA polymerase theta, or Pol?. Pol? is a synthetic lethal target associated with homologous recombination deficiency (HRD) tumors, including those with BRCA1/2 mutations or other genomic alterations.

Data suggest that RP-3467 works synergistically with therapies that result in double stranded DNA breaks, such as PARP inhibition, radioligand therapy and multiple chemotherapies and antibody-drug conjugates (ADCs). Additionally, initial data suggest that Pol? inhibition may interfere with mechanisms central to the development of PARPi resistance.

RP-1664 Highlights: RP-1664 is a highly potent, selective and bioavailable PLK4 inhibitor that is synthetic lethal with TRIM37 gain of function. RP-1664 demonstrated robust and dose-dependent monotherapy activity in multiple TRIM37-high preclinical models across a variety of tumor types, including breast cancer, non-small cell lung cancer (NSCLC) and neuroblastoma. The Company plans to initiate a Phase 1 dose escalation study of RP-1664 in adult and adolescent patients with TRIM37-high solid tumors in the first half of 2024.

RP-3467 Data Highlights: RP-3467 is a highly potent and selective inhibitor of the Pol? helicase domain. RP-3467 demonstrates synergy with PARP inhibitor activity, resulting in durable, complete tumor regressions in multiple preclinical models.

Preclinical studies also show combination potential with multiple other modalities, including RLT, chemotherapy and ADCs. The Company plans to initiate a Phase 1 dosing finding clinical trial of RP-3467 in the second half of 2024.