title: Preclinical in vitro and in vivo evaluation of the potent and specific cyclin-dependent kinase 2 inhibitor NU6102 and a water soluble prodrug NU6301.
abstract: To facilitate the evaluation of CDK2 (cyclin-dependent kinase 2) as a cancer target, the in vitro and in vivo properties of NU6102 (O⁶-cyclohexylmethyl-2-(4'-sulphamoylanilino)purine) and a water soluble prodrug (NU6301) were investigated. NU6102 selectively inhibited the growth of CDK2 WT (wild type) versus KO MEFs (knockout mouse embryo fibroblasts) (GI₅₀ (concentration required to inhibit cell growth by 50%) 14 μM versus >30 μM), and was more growth-inhibitory in p53 mutant or null versus p53 WT cells (p=0.02), and in Rb (retinoblastoma protein) WT SKUT-1B versus SKUT 1 Rb deficient cells (p=0.01). In SKUT-1B cells NU6102 induced a G2 arrest, inhibition of Rb phosphorylation and cytotoxicity (LC₅₀ 2.6 μM for a 24h exposure). The prodrug NU6301 rapidly generated NU6102 in vitro in mouse plasma, and tumour NU6102 levels in vivo consistent with activity in vitro. Eight or 12 hourly dosing of 120 mg/kg NU6301 for 10 days was well tolerated in SKUT-1B tumour-bearing mice and inhibited Rb phosphorylation in tumour tissue. Two (8 hourly dosing) and 3 (12 hourly dosing) day tumour growth delay was observed (p=0.04 and p=0.007, respectively) following NU6301 administration. NU6102 and its prodrug NU6301 have pharmacological properties consistent with CDK2 inhibition, and represent useful tool molecules for the evaluation of CDK2 as a target in cancer.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.forename: Celine
authors.initials: C
authors.lastname: Roche
authors.forename: Johanne
authors.initials: J
authors.lastname: Bentley
authors.forename: Yuzhu
authors.initials: Y
authors.lastname: Cheng
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D011687:Purines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C466914:NU6102; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D011687:Purines; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051357:Cyclin-Dependent Kinase 2