title: A proteome-wide CDK/CRK-specific kinase inhibitor promotes tumor cell death in the absence of cell cycle progression.
abstract: The identification of molecular determinants of tumor cell survival is an important objective in cancer research. Here, we describe a small-molecule kinase inhibitor (RGB-286147), which, besides inhibiting tumor cell cycle progression, exhibits potent cytotoxic activity toward noncycling tumor cells, but not nontransformed quiescent fibroblasts. Extensive yeast three-hybrid (Y3H)-based proteome/kinome scanning with chemical dimerizers revealed CDK1/2/3/5/7/9 and the less well-characterized CDK-related kinases (CRKs) p42/CCRK, PCTK1/3, and PFTK1 as its predominant targets. Thus, RGB-286147 is a proteome-wide CDK/CRK-specific kinase inhibitor whose further study could yield new insight into molecular determinants of tumor cell survival. Our results also suggest that the [1, 3, 6]-tri-substituted-pyrazolo[3,4-d]-pyrimidine-4-one kinase inhibitor scaffold is a promising template for the rational design of kinase inhibitors with potential applications to disease indications other than cancer, such as neurodegeneration, cardiac hypertrophic growth, and AIDS.
authors.affiliation: GPC Biotech, Inc., Waltham, Massachusetts 02451, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Caligiuri
authors.forename: Frank
authors.initials: F
authors.lastname: Becker
authors.forename: Krishna
authors.initials: K
authors.lastname: Murthi
authors.forename: Faith
authors.initials: F
authors.lastname: Kaplan
authors.forename: Severine
authors.initials: S
authors.lastname: Dedier
authors.forename: Christine
authors.initials: C
authors.lastname: Kaufmann
authors.forename: Andy
authors.initials: A
authors.lastname: Machl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zybarth
authors.forename: Judson
authors.initials: J
authors.lastname: Richard
authors.forename: Nick
authors.initials: N
authors.lastname: Bockovich
authors.forename: Art
authors.initials: A
authors.lastname: Kluge
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000145:classification / Q000494:pharmacology*; D020543:Proteome / Q000187:drug effects*; D011743:Pyrimidines / Q000145:classification / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D020543:Proteome; D011743:Pyrimidines; C015482:protein kinase modulator; D018844:Cyclin-Dependent Kinases