title: CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but not Cdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation.
abstract: Tryptamine derivatives, non-planar and potentially less toxic analogues of the anti-cancer agent fascaplysin, have been synthesised. They specifically inhibit Cdk4-D1 vis a vis Cdk2-A but, unlike fascaplysin, do not bind or intercalate DNA. CA224 is the most potent compound identified (Cdk4-D1 IC(50) approximately 5.5 microM). As would be expected of a Cdk4 inhibitor that does not inhibit Cdk2, it maintains a G(0)/G(1) block in synchronised cancer cells and inhibits Cdk4-specific phosphorylation of the retinoblastoma protein.
authors.affiliation: Leicester School of Pharmacy, De Montfort University, UK.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mahale
authors.forename: Carine
authors.initials: C
authors.lastname: Aubry
authors.forename: A
authors.initials: A
authors.lastname: James Wilson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Jenkins
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sutcliffe
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D016193:G1 Phase; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010766:Phosphorylation; D016192:Resting Phase, Cell Cycle; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D004247:DNA; D007211:Indoles; D016160:Retinoblastoma Protein; C513950:CA 224; C069346:fascaplysine; D000644:Quaternary Ammonium Compounds; D002243:Carbolines; D007212:Indolizines