title: Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors.
abstract: The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound αSβR-21 inhibits CDK2/cyclin E with IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 μM, and CDK9-cyclinT with IC(50)=0.11 μM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 μM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.
authors: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, UK.
authors: Stuart C
authors: SC
authors: Wilson
authors: Butrus
authors: B
authors: Atrash
authors: Clare
authors: C
authors: Barlow
authors: Susan
authors: S
authors: Eccles
authors: Peter M
authors: PM
authors: Fischer
authors: Angela
authors: A
authors: Hayes
authors: Lloyd
authors: L
authors: Kelland
authors: Wayne
authors: W
authors: Jackson
authors: Michael
authors: M
authors: Jarman
authors: Amin
authors: A
authors: Mirza
authors: Javier
authors: J
authors: Moreno
authors: Bernard P
authors: BP
authors: Nutley
authors: Florence I
authors: FI
authors: Raynaud
authors: Peter
authors: P
authors: Sheldrake
authors: Mike
authors: M
authors: Walton
authors: Robert
authors: R
authors: Westwood
authors: Steven
authors: S
authors: Whittaker
authors: Paul
authors: P
authors: Workman
authors: Edward
authors: E
authors: McDonald
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077546:Roscovitine; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000621592:CCT68127; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D000241:Adenosine