Discovery of DA1 as PARP inhibitor for the treatment of BRCA-proficient triple negative breast cancer by suppressing the PI3K/AKT/mTOR signaling pathway.

Currently, PARP inhibitors (PARPis) have been primarily utilized to treat ‌breast cancer susceptibility gene (BRCA)-mutated triple-negative breast cancer (TNBC), but their application scope is quite narrow. Recently, it has been discovered that suppression of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway sensitizes BRCA-proficient TNBC to PARPis. In the study, a new PARP inhibitor DA1, modulating PI3K/AKT/mTOR pathway, was designed and synthesized. DA1 showed good antiproliferative effects on BRCA-proficient TNBC cells MDA-MB-231, BT549 and MDA-MB-468, with IC50 values of 0.77 ± 0.03, 1.33 ± 0.01 and 0.28 ± 0.02 μM, respectively. Moreover, DA1 potently inhibited PARP-1 and PARP-2, with IC50 values of 2.5 ± 0.8 and 1.4 ± 0.5 nM respectively. Mechanistically, DA1 suppressed the PI3K/AKT/mTOR signaling pathway, increased DNA damage, caused cell cycle arrest in G2/M phase, and accelerated MDA-MB-231 apoptosis. Additionally, DA1 efficiently suppressed MDA-MB-231 cell migration and invasion. It also exhibited remarkable anti-tumor activity in an MDA-MB-231 cell-derived xenograft model at a dose of 20 mg/kg, with significantly superior therapeutic effects compared to Olaparib, Tan IIA or the combo. Overall, DA1 presents a promising lead compound used to treat BRCA-proficient TNBC.