oral PARP1-DNA selective trapper
1 mpk QD in PDX model, phase I/II, cancer
from literature starting point
Journal of Medicinal Chemistry
AstraZeneca
The AstraZeneca PARP1-DNA trapper, AZD5305, is a phase I candidate (NCT04644068) for cancer that is selective for PARP1 over PARP2 (>500x). Their study began by profiling the existing clinical and late-stage PARP inhibitors in vitro, finding that the seven leading compounds (olaparib, rucaparib, niraparib, talazoparib, veliparib, NMS-P118 and FR257531) having varying levels of low to modest selectivity for PARP1 over PARP2. Building on the high selectivity of compound FR257531, the authors optimized potency against BRCA mutant cancer cells, mitigated hERG issues, lowered log D, optimized intrinsic clearance, and removed the phenyl tetrahydropyridine structural alert (MPTP metabolizes to MPP+, which irreversibly causes Parkinson’s disease in animals). The candidate appears to have reduced effects on bone marrow progenitor cells in vitro, and it will…