AUTHOR=Qin Hongyu , Zhang Jian , Zhao Yilu , Zhang Lihui , Feng Jinhong , Zhang Lei 

TITLE=Discovery of a potent olaparib–chlorambucil hybrid inhibitor of PARP1 for the treatment of cancer

JOURNAL=Frontiers in Pharmacology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1054616

DOI=10.3389/fphar.2022.1054616

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Development of Poly (ADP-ribose) polymerase (PARP) inhibitors has been extensively studied in cancer treatment. Olaparib, the first approved PARP inhibitor, showed potency in the inhibition of both BRCA (breast cancer associated)-mutated and BRCA-unmutated cancers.</p><p><bold>Methods:</bold> Aiming to the discovery of olaparib analogs for the treatment of cancer, structural modifications were performed based on the scaffold of olaparib. In the first series, reduction of carbonyl group to CH<sub>2</sub> led to decrease of PARP1 inhibitory activity. Preserving the original carbonyl group, molecules with potent PARP1 inhibitory activities were derived by introduction of hydrazide and aromatic nitrogen mustard groups. The synthesized compounds were evaluated in the in the PARP1 enzyme inhibitory screening, cancer cell based antiproliferative assay, cell cycle arrest and apoptosis studies.</p><p><bold>Results:</bold> It is remarkable that, molecule <bold>C2</bold> with chlorambucil substitution, exhibited potent PARP1 inhibitory activity and a broad-spectrum of anticancer potency in the <italic>in vitro</italic> antiproliferative assay. Compared with olaparib and chlorambucil, molecule <bold>C2</bold> also showed significant potency in inhibition of a variety of BRCA-unmutated cell lines. Further analysis revealed the effects of <bold>C2</bold> in induction of G2/M phase cell cycle arrest and promotion of apoptosis.</p><p><bold>Discussion:</bold> Collectively, the olaparib-chlorambucil hybrid molecule <bold>(C2)</bold> could be utilized as a lead compound for further drug design.</p>