title: Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases.
abstract: The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (4a) was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells. Although 4a is a competitive inhibitor with respect to ATP, a screen of approximately 50 diverse protein kinases demonstrated that it has high selectivity for Pim kinases. Computational docking of 4a to Pim-1 provided a model for lead optimization, and a series of substituted thiazolidine-2,4-dione congeners was synthesized. The most potent new compounds exhibited IC(50)s of 13 nM for Pim-1 and 2.3 microM for Pim-2. Additional compounds in the series demonstrated selectivities of more than 2500-fold and 400-fold for Pim-1 or Pim-2, respectively, while other congeners were essentially equally potent toward the two isozymes. Overall, these compounds are new Pim kinase inhibitors that may provide leads to novel anticancer agents.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Zuping
authors.initials: Z
authors.lastname: Xia
authors.forename: Christian
authors.initials: C
authors.lastname: Knaak
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Zanna M
authors.initials: ZM
authors.lastname: Beharry
authors.forename: Campbell
authors.initials: C
authors.lastname: McInnes
authors.forename: Wenxue
authors.initials: W
authors.lastname: Wang
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D002460:Cell Line; D002474:Cell-Free System; D020650:Combinatorial Chemistry Techniques; D005260:Female; D006801:Humans; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim