Design, synthesis and pharmacological evaluation of new PARP1 inhibitors by merging pharmacophores of olaparib and the natural product alantolactone

Abstract

Based on the reported synthetic lethality of the combination of PARP inhibitor olaparib with the natural product alantolactone, we designed several series of new PARP1 inhibitors by structurally merging both compounds into a single hybrid compound. Among them, compounds 20e and 25a displayed not only high biochemical activity (IC₅₀ = 2.99 nM and 5.91 nM vs 11.36 nM), but also higher inhibitory effects against proliferation of BRCA1-deficient UWB1.289 cells than olaparib (IC₅₀ = 0.27 μM and 0.41 μM vs 0.66 μM). Much weak activity was observed in BRCA1 wild-type human fetal lung IMR-90 and WI-38 cells (IC₅₀s > 10 μM). Treatment with compounds 20e and 25a was found to induce increased levels of γH2AX in a concentration-dependent manner in both MDA-MB-436 and Capan-1 cells to a degree comparable with that of olaparib. Further mechanism study indicated that these compounds activated the cell cycle checkpoints, and subsequently induced G2/M arrest and apoptosis. The results validated that merging PARP inhibitors with other DNA-damage related compounds would produce more potent PARP inhibitors for anticancer studies. However, the poor aqueous solubility and low cell penetration of the current hybrid compounds call for further structural optimization.

Keywords: Alantolactone; BRCA1/2 mutant; Olaparib; PARP1; Synthetic lethality.