1. Academic Validation
  2. N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2

N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2

  • J Med Chem. 2004 Jul 15;47(15):3710-22. doi: 10.1021/jm0311442.
Ian R Hardcastle 1 Christine E Arris Johanne Bentley F Thomas Boyle Yuzhu Chen Nicola J Curtin Jane A Endicott Ashleigh E Gibson Bernard T Golding Roger J Griffin Philip Jewsbury Jerome Menyerol Veronique Mesguiche David R Newell Martin E M Noble David J Pratt Lan-Zhen Wang Hayley J Whitfield
Affiliations

Affiliation

  • 1 Northern Institute for Cancer Research, Bedson Building, School of Natural Sciences, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK. I.R.Hardcastle@ncl.ac.uk
Abstract

The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15569
    99.23%, CDK1/CDK2 抑制剂
    CDK