title: Identification and characterization of a novel integrin-linked kinase inhibitor.
abstract: Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC(50), 0.6 μM), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC(50), 1-2.5 μM), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3β and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Su-Lin
authors.initials: SL
authors.lastname: Lee
authors.forename: En-Chi
authors.initials: EC
authors.lastname: Hsu
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chou
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Chuang
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Bai
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000099200:Scaffold Protein ILK
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D018719:Erb-b2 Receptor Tyrosine Kinases; D051840:Y-Box-Binding Protein 1; D000099200:Scaffold Protein ILK; C562238:N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-(1,1'-biphenyl)-4-yl)-1H-pyrazol-3-yl)propanamide