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Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

The rational design of cyclin-dependent protein kinase (CDK) inhibitors presumes the development of approaches for accurate prediction of selectivity and the activity of small molecular weight anticancer drug candidates. Aiming at attenuation of general toxicity of low selectivity compounds, we herein explored the new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. Newly synthesized compounds 1-4 containing an aliphatic methyl group or aromatic radicals at the periphery of the scaffold were analyzed for the prediction of relative free energies of binding to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics. This methodology allows for the demonstration of a good correlation between the calculated parameters of interaction of 1-4 with individual targets and the values of inhibitory potencies in in vitro kinase assays. We provide evidence in support of NEQ thermodynamics as a time sparing, precise, and productive approach for generating chemical inhibitors of clinically relevant anticancer targets.

 

Comments:

The text you provided discusses the rational design of cyclin-dependent protein kinase (CDK) inhibitors, focusing on the development of methods for predicting selectivity and activity of potential anticancer drug candidates. The researchers explored a new chemotype of imidazole-4-N-acetamide substituted derivatives of the pan-CDK inhibitor PHA-793887. These newly synthesized compounds were analyzed for their binding energies to CDK1, -2, -5, and -9 using a protocol based on non-equilibrium (NEQ) thermodynamics.

In simpler terms, the researchers developed and tested new compounds that could potentially inhibit CDKs, which are proteins involved in regulating cell division. They used a method based on non-equilibrium thermodynamics to predict how well these compounds would bind to specific CDKs. The study found a good correlation between the calculated binding parameters and the actual inhibitory potency observed in laboratory experiments. This suggests that the NEQ thermodynamics method is a promising and efficient approach for designing chemical inhibitors targeted at anticancer proteins, saving time and resources in the drug discovery process.

Related Products

Cat.No. Product Name Information
S1487 PHA-793887 PHA-793887 is a novel and potent inhibitor of CDK2, CDK5 and CDK7 with IC50 of 8 nM, 5 nM and 10 nM. It is greater than 6-fold more selective for CDK2, 5, and 7 than CDK1, 4, and 9. PHA-793887 induces cell-cycle arrest and apoptosis. Phase 1.

Related Targets

Apoptosis related CDK