title: Development of novel ACK1/TNK2 inhibitors using a fragment-based approach.
abstract: The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 μM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).
authors.affiliation: §Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.affiliation: §Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mahajan
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.forename: Daniel
authors.initials: D
authors.lastname: Zhang
authors.forename: Nathan
authors.initials: N
authors.lastname: Tindall
authors.forename: Miles
authors.initials: M
authors.lastname: Huseyin
authors.forename: Harsukh
authors.initials: H
authors.lastname: Gevariya
authors.forename: Sakib
authors.initials: S
authors.lastname: Kazi
authors.forename: Sevil
authors.initials: S
authors.lastname: Ozcan
authors.affiliation: §Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
authors.affiliation: §Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human