Crystal Structure of Human Cyclin-Dependent Kinase 2 in Complex with the Adenine-Derived Inhibitor H717

Abstract

Cyclin-dependent kinases (CDKs) are regulatory proteins of the eukaryotic cell cycle. They act after association with different cyclins, the concentrations of which vary throughout the progression of the cell cycle. As central mediators of cell growth, CDKs are potential targets for inhibitory molecules that would allow disruption of the cell cycle in order to evoke an antiproliferative effect and may therefore be useful as cancer therapeutics. We synthesized several inhibitory 2,6,9-trisubstituted purine derivatives and solved the crystal structure of one of these compounds, H717, in complex with human CDK2 at 2.6 A resolution. The orientation of the C2-p-diaminocyclohexyl portion of the inhibitor is strikingly different from those of similar moieties in other related inhibitor complexes. The N9-cyclopentyl ring fully occupies a space in the enzyme which is otherwise empty, while the C6-N-aminobenzyl substituent points out of the ATP-binding site. The structure provides a basis for the further development of more potent inhibitory drugs.

Antiproliferative activity of olomoucine II, a novel 2,6,9-trisubstituted purine cyclin-dependent kinase inhibitor

“…1). The purine ring system of the ligand binds differently to the purine portion of ATP but in comparison with other homologous ligand structures (Protein Data Bank codes 1CKP and 1G5S [8,37]), the purine ring is found to be in almost exactly the same position. The published binding modes and descriptions for both olomoucine and roscovitine [36,38] also show that these compounds bind in a very similar mode to that of olomoucine II (coordinates for the two structures are not available).…”

“…Since a method for CDK9 crystallization has not yet been described, a co-crystal of olomoucine II with CDK2 was analyzed to gain better insight into the inhibition specificity. The olomoucine II molecule occupies almost exactly the same position in CDK2 compared with other homologous ligand complex structures such as those of purvalanol B, olomoucine, H717, and roscovitine [8,[36][37][38]. In the olomoucine II structure, the phenolic hydroxyl forms an intramolecular hydrogen bond to N1 of the purine ring system and this stabilizes the orientation of the ring.…”

p42/p44 MAPKs are intracellular targets of the CDK inhibitor purvalanol

“…So far, numerous specific CDK inhibitors have been identified on the basis of their ability to inhibit CDK1, CDK2 or CDK4: the purines olomoucine (Vesely et al, 1994), roscovitine de Azevedo et al, 1997); purvalanols (Gray et al, 1998;Chang et al, 1999;Villerbu et al, 2002), CVT-313 (Brooks et al, 1997), C2-alkylynated purines (Legraverend et al, 2000), H717 (Dreyer et al, 2001) and NU2058 (Arris et al, 2000), piperidine-substituted purines (Shum et al, 2001), toyocamycin (Park et al, 1996), flavopiridol (Losiewicz et al, 1994), indirubins (Hoessel et al, 1999;Leclerc et al, 2001), paullones Zaharevitz et al, 1999;Leost et al, 2000), g-butyrolactone (Kitagawa et al, 1993), hymenialdisine , indenopyrazoles (Nugiel et al, 2001), the pyrimidines NY6027 (Arris et al, 2000) and CGP60474 (Zimmermann, 1995), pyridopyrimidines (Barvian et al, 2000), the aminopyrimidine PNU 112455A (Clare et al, 2001), oxindoles (Kent et al, 1999;Davis et al, 2001), PD0183812 (Fry et al, 2001), cinnamaldehydes (Jeong et al, 2000), quinazolines (Shewchuk et al, 2000;Sielecki et al, 2001), fasclaplysin (Soni et al, 2000(Soni et al, , 2001, SU9516 (Lane et al, 2001) and benzocarbazoles (Carini et al, 2001). Despite their chemical diversity, these inhibitors all act by competing with ATP at the ATP-binding site of the kinase.…”

Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities

“…Successive studies lead to the development of derivatives with enhanced efficiency as Purvalanol (III), Olomoucine II (IV) (Fig. 1) (Havlicek et al, 1997;Dreyer et al, 1998;Gray et al, 1998;Haesselein and Jullian, 2002;Krystof et al, 2002).…”