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: Huw D Thomas, Lan-Zhen Wang, Celine Roche, Johanne Bentley, Yuzhu Cheng, Ian R Hardcastle, Bernard T Golding, Roger J Griffin, Nicola J Curtin, David R Newell
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 47 Issue 13 Pg. 2052-9 (Sep 2011) ISSN: 1879-0852 [Electronic] England
• PMID: 21570822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• NU6102
• Prodrugs
• Protein Kinase Inhibitors
• Purines
• Retinoblastoma Protein
• Tumor Suppressor Protein p53
• Cyclin-Dependent Kinase 2

Topics

• Animals
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors)
• Female
• HCT116 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Prodrugs (pharmacokinetics, pharmacology)
• Protein Kinase Inhibitors (pharmacokinetics, pharmacology)
• Purines (pharmacokinetics, pharmacology)
• Retinoblastoma Protein (metabolism)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays