Discovery of a Novel Series of Benzimidazoles/Purines as Potent, Selective and Orally Active Inhibitors of the DNA Polymerase Activity of POLQ.

DNA polymerase θ (Polθ, gene POLQ) is a key enzyme in the microhomology-mediated end joining (MMEJ) pathway to repair DNA double strand breaks (DSB). Here we report the discovery of novel, potent, selective and orally active inhibitors of the DNA polymerase activity of POLQ. Starting from a weak inhibitor of POLQ (compound 1, IC50 0.8 μM, biochemical assay), further optimization of the series led to compound 37, a potent inhibitor of POLQ (IC50 < 0.003 μM, biochemical assay), which suppressed the cellular MMEJ pathway activity (IC50 0.10 μM), showed anti-proliferative activity in homologous recombination repair (HRR) deficient cell lines (e.g. BRCA2-/- DLD-1 IC50 0.058 μM), and enhanced antiproliferative activity of the PARP 1/2 inhibitor olaparib in multiple HRR defective cell lines, with no activity in HRR proficient settings. Compound 37 showed tumor regression in the BRCA2-/- DLD-1 murine xenograft model after chronic oral dosing in combination with olaparib.