Replacing saruparib's carboxamide yields an oral, brain-penetrant PARP1-selective inhibitor
- Aimed at CNS malignancies, the program replaced the carboxamide of saruparib with a series of heterocycles, targeting PARP1 over PARP2 to limit haematological toxicity.
- Caco-2 efflux, rather than the usual MDR1-MDCK assay, was used as a progression filter to select compounds with good unbound brain exposure.
- The lead compound was orally bioavailable and caused tumour regression in xenografts at a low dose, with a projected low clinical dose.
💡 Points
Swapping the primary carboxamide is a bold move, since that group anchors the nicotinamide pocket, and the heterocycles evidently kept the binding. The more useful lesson is the filter: if Caco-2 efflux predicts unbound brain exposure better than MDR1-MDCK, plenty of CNS programs may be discarding good compounds.