Oral POLQ polymerase inhibitors regress BRCA2-null tumors with olaparib
- POLQ drives microhomology-mediated end joining, making it a synthetic-lethal target in homologous-recombination-deficient cancers.
- Optimizing a weak biochemical hit gave benzimidazole/purine inhibitors; compound 37 is potent, selective and orally active.
- In BRCA2-deficient DLD-1 cells it was antiproliferative and boosted olaparib, with no effect in HR-proficient cells; chronic oral dosing with olaparib regressed xenografts.
💡 Points
A polymerase-domain inhibitor that is both oral and selective for the HR-deficient setting is what this target has been missing. The HR-proficient null result is the key control, so I'd now look at resistance and how it stacks against the helicase-domain approaches.