CDK2 inhibitors

Fig. 1.10 Cdk2 inhibitor identified using NMR screening by the WaterLOGSY method.

Renato, C., Alzate-Morales, J. H., William, T., Santos Juan C., and Ca rdenas, C. 2007. Theoretical study on CDK2 inhibitors using a global softness obtained from the density of states. J. Phys. Chem. B 111(12) 3293-3297. 

Agouron (now Pfizer) disclosed in a series of patents the discovery of potent CDK inhibitors based on the 5-benzoyl-2,4 diaminothiazole template [130, 131]. Compounds 66 and 67 were both potent CDK2 inhibitors (66 Ki < 0.005 xM 67 Ki = 0.10 xM), but these compounds varied in their activity... 

Building from the initial Cdk2 inhibitors, Kolonin and Finley derived peptide aptamers that inhibit two Cdks from Drosophila mdanogaster, DmCdkl and DmCdk2 [83], They then showed that expression of these peptides in Drosophila mdanogaster mi-... 

FIGURE 10.1 Pharmacophore model representation derived from the cycUn-dependent kinase 2 (CDK2) inhibitor 3- [(2,2-Dioxido-l,3-dihydro-2-benzothien-5-yl)amino]-methylene -5-(l,3-oxazol-5-yl)-l,3"dihydro-2H-indol-2-one in its binding site, PDB entry Ike processed using LigandScout ... 

FIGURE 30.6 Examples of protein crystals. From left to right (3-secretase inhibitor complex human farnesyl pyrophosphatase in complex with the nitrogen-containing bisphosphonate drug zoledronic acid Crystals of the Abl kinase domain in complex with imatinib - Source Courtesy of S.W. Cowan-Jacob, Novartis Institutes for BioMedical Research crystal of a Cdk2 inhibitor complex. 

Fig. 4.4 SCAMPI analysis of a series of CDK2 inhibitors, (a) Full tree with one node highlighted, (b) enlarged picture of one node and...

Garda-Sosa, A.T. and Mancera, R.L. (2006) The effect of a tightly bound water molecule on scaffold diversity in the computer-aided de novo ligand design of CDK2 inhibitors. Journal of Molecular Modeling, 12, 422—431. 

Carboxylic esters are often unstable in vivo consequently many different bioisosteres for this functional group have been tried, most of them being small heterocycles. For a series of CDK2 inhibitors like 4 (Figure 8.10) this problem could be overcome through the use of an... 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

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