Substitution of the cyano-NNO-azoxy moiety (NC-N=(O)N-) for the nitroso group in NU6027, a potent and selective CDK2 inhibitor, affords a compound with slightly improved potency and comparable selectivity profile. A molecular modelling study indicates for this new scaffold a binding mode similar to the one adopted by other purine and pyrimidine analogues, and suggests a relevant role for a conserved water molecule in stabilizing the bioactive pose of this and other pyrimidine ligands. The introduction of aminosulfonylphenyl substituents on the 2-amino group of the pyrimidine increased the CDK2 inhibitory potency by two orders of magnitude, while maintaining the same degree of selectivity.

6-Cyclohexylmethoxy-5-(cyano-NNO-azoxy)pyrimidine-4-amine: A new scaffold endowed with potent CDK2 inhibitory activity

BOSCHI, Donatella;TOSCO, Paolo;FRUTTERO, Roberta;GASCO, Alberto
2013

Abstract

Substitution of the cyano-NNO-azoxy moiety (NC-N=(O)N-) for the nitroso group in NU6027, a potent and selective CDK2 inhibitor, affords a compound with slightly improved potency and comparable selectivity profile. A molecular modelling study indicates for this new scaffold a binding mode similar to the one adopted by other purine and pyrimidine analogues, and suggests a relevant role for a conserved water molecule in stabilizing the bioactive pose of this and other pyrimidine ligands. The introduction of aminosulfonylphenyl substituents on the 2-amino group of the pyrimidine increased the CDK2 inhibitory potency by two orders of magnitude, while maintaining the same degree of selectivity.
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CDK inhibitor; CDK2 selective inhibitor; Cyano-NNO-azoxy; 5-substituted pyrimidine-4-amine; water-mediated hydrogen bond
Boschi D.; Tosco P.; Chandra N.; Chaurasia S.; Fruttero R.*; Griffin R.; Wang L.-Z.; Gasco A.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/138734
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