title: Non-NAD-Like poly(ADP-Ribose) Polymerase-1 Inhibitors effectively Eliminate Cancer in vivo.
abstract: The clinical potential of PARP-1 inhibitors has been recognized >10years ago, prompting intensive research on their pharmacological application in several branches of medicine, particularly in oncology. However, natural or acquired resistance of tumors to known PARP-1 inhibitors poses a serious problem for their clinical implementation. Present study aims to reignite clinical interest to PARP-1 inhibitors by introducing a new method of identifying highly potent inhibitors and presenting the largest known collection of structurally diverse inhibitors. The majority of PARP-1 inhibitors known to date have been developed as NAD competitors. NAD is utilized by many enzymes other than PARP-1, resulting in a trade-off trap between their specificity and efficacy. To circumvent this problem, we have developed a new strategy to blindly screen a small molecule library for PARP-1 inhibitors by targeting a highly specific rout of its activation. Based on this screen, we present a collection of PARP-1 inhibitors and provide their structural classification. In addition to compounds that show structural similarity to NAD or known PARP-1 inhibitors, the screen identified structurally new non-NAD-like inhibitors that block PARP-1 activity in cancer cells with greater efficacy and potency than classical PARP-1 inhibitors currently used in clinic. These non-NAD-like PARP-1 inhibitors are effective against several types of human cancer xenografts, including kidney, prostate, and breast tumors in vivo. Our pre-clinical testing of these inhibitors using laboratory animals has established a strong foundation for advancing the new inhibitors to clinical trials.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Yingbiao
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Niraj
authors.initials: N
authors.lastname: Lodhi
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Kotova
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Aaron Dan
authors.initials: AD
authors.lastname: Pinnola
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Golovine
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Makhov
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Kate
authors.initials: K
authors.lastname: Pechenkina
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kolenko
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, United States. Electronic address: Alexei.Tulin@fccc.edu.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tulin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D054852:Small Molecule Libraries; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D054852:Small Molecule Libraries; D009243:NAD; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Cancer cells; Histone-dependent PARP-1 regulation; PARP-1; PARP-1 inhibitors; Poly(ADP-ribose)