Structure-Based design of 2-Arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-Dependent kinases 1 and 2

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…The resolution of the X-ray structure of the kinase domain of PDK1 with BX-320 revealed a classical two H-bond interactions between the hinge region-the amino-acid backbone of Ala-162-of the enzyme and two of the aminopyrimidine nitrogens of the inhibitor. In this context, the mode of binding of BX-320 is similar to the one reported for aminopyridines in complex with cyclin-dependent kinase 2/cyclin A (Sayle et al, 2003). The BX series of molecules has not yet entered into the clinical trials at the time of this review.…”

Novel Structural Features of CDK Inhibition Revealed by an ab Initio Computational Method Combined with Dynamic Simulations

“…In the particular case of SU9516, the observed selectivity had previously been proposed to arise from an interaction with the CDK2 specific residue Lys89 [31], but no such interaction was found in a recent crystallographic study [32]. Indeed, the Lys89 residue was also a target for the two derivatives mentioned above, NU6102 and 9d-NU6027, but again no such interaction has been observed in the crystallographic studies performed [17,30].…”

“…These provide a clear picture of the binding features between the ligand and those residues that constitute the binding pocket, revealing the dominant interactions to be hydrogen bonding, electrostatic and van der Waals forces. Potent lead compounds for new CDK inhibitors have been readily developed by taking advantage of these interactions via analysis of the so-called structure-activity relationship [12,[15][16][17][18]. In addition, computeraided approaches such as database [19], docking [20][21][22] and scoring function methods [23] provide an effective way of probing the binding modes and testing the binding strength of large arrays of molecules, and thus help identify potential new lead compounds.…”

“…With the goal of increasing the protein-inhibitor interactions, specific functional groups have been added to O 6 -cyclohexylmethylguanine (NU2058) [29] to develop its more potent variant O 6 -cyclohexylmethoxy-2-(4'-sulfamoylanilino)purine (NU6102) [30], and to 2,6-diamino-4-cyclohexylmethyloxy-5-nitrosopyrimidine (NU6027) [29] to obtain a potent carboxamide derivative (the 9d variant in [17]) (see Figure 1). Structural investigations demonstrated that the higher potency of these two variants is due to formation of additional interactions with the polar residue Asp86, while the "standard" triplet of hydrogen bonds is retained [17,30]. A puzzling exception is 3-(3H-Imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516) which appears to form only the standard hydrogen bond triplet but is highly potent and also presents a good degree of selectivity for CDK2 against CDK4 [31,32].…”

“…This is defined as the equilibrium dissociation constant for the reaction of an inhibitor with a protein to form an inhibitor-protein complex. Under the same assay conditions, K i and IC 50 values are related via a simple proportionality relationship [33], so that often the values can be directly compared [17]. Therefore, both IC 50 and K i values can be assumed to be directly related to the free energy change associated with the inhibitor binding to the protein [30].…”