Structurally unique PARP‐1 inhibitors for the treatment of prostate cancer

Abstract

The prognosis for metastatic castration-resistant prostate cancer is unfavorable, and although Poly(ADP)-ribose polymerase-1 (PARP-1) inhibitors have shown efficacy in the treatment of androgen-receptor dependent malignancies, the limited number of options present obstacles for patients that are not responsive to these treatments.Here we utilize an integrated screening strategy that combines cellular screening assays, informatics, in silico computational approaches, and dose-response testing for reducing a compound library of confirmed PARP-1 inhibitors. Six hundred and sixtyfour validated PARP-1 inhibitors were reduced to 9 small molecules with favorable physicochemical/ADME properties, unique chemical fingerprints, high dissimilarity to existing drugs, few off-target effects, and dose-responsivity in the 1 µmol/L -20 µmol/L range. The top 9 unique molecules identified by our integrated screening strategy will be selected for further preclinical development including cytotoxicity testing, effects on mitosis, structure-activity relationship, physicochemical/ADME studies, and in vivo testing. K E Y W O R D SPARP-1, PARP-1 inhibitors, poly(ADP-ribose), prostate cancer cells

Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy

“…To overcome the limitation of NAD-like PARP-1 inhibitors, we developed a novel class of non-NAD-like PARP-1 inhibitors based on the molecular mechanism underlying PARP-1-dependent transcription with non-NAD like structure [ 23 , 24 , 25 ]. 5F02 has no obvious structural homologues among components of eukaryotic enzymatic pathways and believed to disrupt PARP-1 binding and activation by histones [ 26 ]. Non-NAD-like nature minimizes off-target effects and ensures greater specificity.…”