Cytokinin-Derived Cyclin-Dependent Kinase Inhibitors:  Synthesis and cdc2 Inhibitory Activity of Olomoucine and Related Compounds

Havlı́cěk, Libor; Hanuš, Jan; Veselý, Jozef; Leclerc, Sophie; Meijer, Laurent; Shaw, G.; Strnad, Miroslav

doi:10.1021/jm960666x

Cited by 223 publications

(157 citation statements)

References 25 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…Both roscovitine and olomoucine exhibit the ability to synergize with FTI to induce apoptosis of human cancer cell lines. The (S)-enantiomer of roscovitine (roscovitine, S-isomer) still retains the ability to e ciently inhibit Cdks (Havlicek et al, 1997). This S-isomer was as active as roscovitine in enhancing FTI-induced caspase-3 activation of HL-60 (unpublished data).…”

Section: Discussionmentioning

confidence: 89%

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

et al. 2000

View full text Add to dashboard Cite

Farnesyltransferase inhibitor (FTI) induces apoptosis of transformed cells. This involves changes in mitochondria, including decrease of mitochondrial membrane potential and the release of cytochrome c. The released cytochrome c then induces events leading to the activation of caspase-3. In this study, we report that purine derivative cyclin-dependent kinase (Cdk) inhibitors, roscovitine and olomoucine, dramatically enhance this FTI-induced apoptosis of human cancer cell lines. We noticed the synergy between Cdk inhibitors and FTI through our screen to identify compounds that enhance FTI-induced apoptosis of promyelocytic leukemic cell line HL-60. The Cdk inhibitors by themselves do not induce apoptosis at the concentrations used. Roscovitine synergizes with FTI to release cytochrome c from mitochondria. In addition, we detected synergistic e ects of FTI and roscovitine to inhibit hyperphosphorylation of retinoblastoma protein. Enhancement of FTI-induced apoptosis by roscovitine is not unique to HL-60 cells, since similar synergy was observed with a leukemic cell line CEM and a prostate cancer cell line LNCaP. In LNCaP cells, in addition to roscovitine and olomoucine, phophatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, was e ective in enhancing FTI-induced apoptosis. However, the e ects of roscovitine appear to be distinct from those of LY294002, since roscovitine did not a ect Akt activity while LY294002 signi®cantly decreased the activity of Akt. Our ®nding of the synergy between FTI and Cdk inhibitor is signi®cant for understanding the mechanism of action of FTI as well as for clinical use of FTI. Oncogene (2000) 19, 3059 ± 3068.

show abstract

Section: Discussionmentioning

confidence: 89%

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

et al. 2000

View full text Add to dashboard Cite

show abstract

“…9 It competes with ATP for its binding site on CDKs and as such is a member of a large class of similar chemical inhibitors of CDKs. 10 Compounds of this class have been shown to block proliferation of various tumour types in cell culture. [11][12][13] Our study describes the relative potency of CYC202 (R-roscovitine) against purified recombinant CDKs and relates this result to in vivo growth inhibitory properties in a panel of human cancer cell lines representative of human solid tumours, and compares its cytotoxicity in proliferating tumour cells vs. non-proliferating cells.…”

mentioning

confidence: 99%

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

McClue

Blake

Clarke

et al. 2002

Intl Journal of Cancer

357

296

View full text Add to dashboard Cite

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC 50 ‫؍‬ 0.10 M) with an average cytotoxic IC 50 of 15.2 M in a panel of 19 human tumour cell lines, and we also demonstrate selectivity for rapidly proliferating cells over non-proliferating cells. A study of the cell cycle effects of CYC202 in Lovo colorectal carcinoma cells showed that the major effect was not the predicted arrest in one part of the cycle, but rather an induction of cell death from all compartments of the cell cycle. The maximum tolerated dose given intravenously to mice was in excess of 20 mg/kg. Doses up to 2,000 mg/kg were tolerated when administered orally in mice. Following repeated intraperitoneal administration (3 times daily for 5 days) of 100 mg/kg to nude mice bearing the Lovo human colorectal tumour, CYC202 induced a significant antitumour effect with a 45% reduction in tumour growth compared to controls. A second experiment using the human uterine xenograft MESSA-DX5 treated with orally administered CYC202 (500 mg/kg 3 times daily for 4 days) also exhibited a significant reduction in the rate of growth of the tumour (62%). These data, showing enzyme and cellular potency together with antitumour activity, confirm the potential of CDK2 inhibitors such as CYC202 as anticancer drugs. © 2002 Wiley-Liss, Inc. Key words: cyclin-dependent kinase inhibitors; CYC202; roscovitine; cell cycle; anti-tumour efficacyCyclin-dependent kinases (CDKs) are key regulators in the process of cell cycle progression. 1 These enzymes are activated by periodic formation of complexes with cyclins, which are proteins that are present only at specific stages of the cell cycle. CDK4 and CDK6, coupled with their partner cyclin D, are responsible for progression through G1, whereas CDK2 in combination with cyclin E is responsible for normal progression from G1 into S phase. CDK2/cyclin A is required for progression through S phase, and CDK1/cyclin B is necessary for mitosis to occur. 2 These CDK/ cyclin complexes are regulated in turn by stoichiometric association with small proteins, cyclin-dependent kinase inhibitors (CDKIs), such as p19, p16, p15, p21 and p27, which are members of the INK4 and WAF1/KIP1 class of CDK inhibitor. Mutation and/or deletion of some of these CDKIs has been shown in many human neoplasias. 3 Hence control of the cell cycle through CDKs, by means of small molecule CDK inhibitors, has been of great interest as a novel cancer treatment strategy. Questions remain, however, regarding the importance of CDK selectivity for this type of agent. Both CDK2 and CDK4 have been targeted for small molecule inhibitor development, and recent results suggest that CDK2 antagonists may induce apoptosis selectively in transformed cells regardless of p53 status, 4 while the function of CDK4 has now been linked to modulation of the rate of cellular growth and has been suggested to be (in Drosophila at least) dispensable for cel...

show abstract

“…We chose as receptors the CDK subunit in the cyclin A-CDK2 (PDB id: 1FIN), activator 1-CDK5 (PDB id: 1UNL) and cyclinV-CDK6 (PDB id: 1XO2) heterodimers respectively. The ligands we tested are those commercially available at www.biomol.com http://www.biomol.com/ and for which IC 50 have been measured: Butyrolactone I. Butyrolactone I is a potent, selective and cell permeable inhibitor of CDKs that inhibits cyclin B-cdc2 (cyclin B-CDK1; IC 50 = 0.68 mM), 44 CDK2 45 and CDK5. 46 A wide range of other kinases are at least 100-fold less sensitive (kinase/IC 50 (mM): MAPK/94; PKC/160; PKA/260; CKII/240; CKI/>590; EGFR/>590).…”

Section: Methodsmentioning

confidence: 99%

“…Roscovitin is a potent inhibitor of cyclin B-CDK1 kinase activity (IC 50 = 0.2 mM). 50,51 Ligand molecules were built with the Maestro graphic interface and minimized with the program LigPrep (both are part of the Schrödinger TM suite, www.schrodinger.com). In silico docking experiments were performed with the program Glide (also part of the Schrödinger TM suite).…”

Section: Methodsmentioning

confidence: 99%

“…As the structure of cyclin D1 is currently unknown, we made a model based on the structure of the viral cyclin K. 20 Prior to run in silico docking experiments on this model, we tested the docking of few known inhibitors, with already characterized IC 50 , on existing structures of CDK2 and CDK6, as a validation of the methods used afterward. We then applied our fragment-based docking approach on the three molecular surface areas of cyclin D1 previously described, and designed a total of four compounds.…”

Section: Structural Basis For the Inhibition Of Cyclin D1mentioning

confidence: 99%

See 1 more Smart Citation

Structural Basis for the Modulation of CDK-Dependent/Independent Activity of Cyclin D1

Ferrer¹,

Dupuy²,

Borel³

et al. 2006

Cell Cycle

View full text Add to dashboard Cite

Cytokinin-Derived Cyclin-Dependent Kinase Inhibitors: Synthesis and cdc2 Inhibitory Activity of Olomoucine and Related Compounds

Cited by 223 publications

References 25 publications

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R‐roscovitine)

Structural Basis for the Modulation of CDK-Dependent/Independent Activity of Cyclin D1

Contact Info

Product

Resources

About