Discovery of novel olaparib-β-carboline hybrids for treating BRCA-deficient triple negative breast cancer.

PARP inhibitors exert effects synergistically with DNA damage agents; therefore, the present work focused on designing and synthesizing novel olaparib-β-carboline hybrids for the treatment of BRCA-deficient TNBC. Among synthesized compounds, compound 6 substituted with methyl at position 1 of β-carboline had the most potent anti-proliferative activity against BRCA-deficient TNBC cells MDA-MB-436, with an IC50 value of 4.38 ± 0.05 μM. Moreover, compound 6 potently inhibited PARP-1 and PARP-2, with IC50 values of 1.6 ± 0.7 and 0.9 ± 0.2 nM, respectively. Mechanistically, compound 6 could increase DNA damage, induce cell cycle arrest in the G2/M phase, and promote MDA-MB-436 apoptosis. Overall, 6 is a potential hybrid molecule and can be a candidate compound for the treatment of BRCA-deficient TNBC.