ATP-site Directed Inhibitors of Cyclin-dependent Kinases

Abstract

Cyclin-dependent kinases trigger and coordinate transitions between different phases the cell division cycle (CDK1, 2, 3, 4, 6, 7). They also play a role in apoptosis (CDK2), in neuronal cells (CDK5) and in the control of transcription (CDK 7, 8, 9). Intensive screening has lead to the recent identification of a series of chemical inhibitors of CDKs: olomoucine, roscovitine, purvalanol, CVT -313, flavopiridol, y­ butyrolactone, indirubins, paullones and staurosporine. Some of these compounds display remarkable selectivities and efficiencies (IC5o < 25 nM). Many have been co-crystallised with CDK2 and their interactions with the kinase have been analysed in atomic detail. These inhibitors all act by competing with ATP for binding at the catalytic site. Most inhibitors present a flat heterocyclic ring system that occupies the purine binding pocket as well as form 2 or 3 hydrogen bonds with Glu-81 and Leu-83. The binding modes of these inhibitors are reviewed in this article. Knowledge of the CDK/inhibitor interactions will be of great help to design inhibitors with improved selectivity our potency as well as to generate affinity chromatography matrices for the purification and identification of their cellular targets. The potential use of CDK inhibitors is being extensively evaluated in cancer chemotherapy and other fields such as the cardiovascular domain (restenosis), dermatology (psoriasis), nephrology (glomerulonephritis) parasitology (unicellular parasites such as Plasmodium, Trypanosomes, Toxoplasm,...etc.), neurology (Alzheimer's disease) and viral infections (cytomegalovirus, H.I.V., herpes).

The influence of natural products upon drug discovery (Antiquity to late 1999)

“…Work from Schultz' group at Berkeley was reported in 1998 128 and then more complete reviews from the same group were published in 1999. 129,130 Comparison of the structures of purvalanols A (83) and B (84) with olomoucine and roscovitine show that only very small changes in the sidechains are enough to alter the IC 50 figures by three orders of magnitude. The interesting aspect, however, is that the base structure is effectively that of the natural products, thus demonstrating the value of using combinatorial chemistry techniques to optimize an existing active structure rather than attempting to synthesize de novo.…”

Density functional study of the enzymatic reaction catalyzed by a cyclin-dependent kinase

“…1 Increasing evidence is arising about the connection between the CDKs regulation and some human diseases. 2,3 Several crystallographic studies have recently disclosed the structural determinants of representative members of this protein family, also providing details at the atomic level about the CDKs molecular mechanism. 4 However, the enzymatic reaction has not yet been investigated in depth.…”

An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors

“…9 depicts the arrangement of CDK2 residues surrounding ATP. 4 By comparison of the PHTPPs-binding pocket as shown in Fig. 5B with this figure, clearly compound 9 overlaps significantly with the hydrophobic adenine and ribose subsites though a small deflection occurs when compared to ATP.…”

“…Important residues involved in the CDK2 ATP-binding site are 10-15, 18, 31, 33, 64, 80-83, 86, 129-133, 145 and 160. 4 Inhibitors that fit well with the ATP binding cleft share common structure features, that is, a planar hydrophobic heterocyclic framework. 76 It is also noted that prominent effects to stabilize the small ligand in the ATP binding pocket are H-bond interactions formed with the hinge region of CDK2, and the hydrophobic contacts.…”

“…CKIs inhibit the catalytic activity of the CDK-cyclin pairs through competitive inhibition or formation of the inactive complexes. 3 In humans, at least 9 CDKs and 10 cyclins have been identified, 4 and the endogenous CKIs are categorized into two groups: the INK4 family and the Kip/Cip family, according to their structures and functions. [5][6][7] The INK4 family (p16 INK4a , p15 INK4b , p18 INK4c and p19 INK4d ) specifically bind to CDK4/CDK6 and inhibits their kinase activities at the mid-G1 phase.…”