Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors

Chang, Young‐Tae; Gray, Nathanael S.; Rosania, Gustavo R.; Sutherlin, Daniel P.; Kwon, Soojin; Norman, Thea; Sarohia, Radhika; Leost, Maryse; Meijer, Laurent; Schultz, Peter G.

doi:10.1016/s1074-5521(99)80048-9

Cited by 273 publications

(236 citation statements)

References 18 publications

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“…Olomoucine has been reported to enhance the induction of apoptosis by a DNA damaging agent mitoxantrone without a ecting cell cycle distribution (Ongkeko et al, 1995). Chang et al (1999) synthesized a variety of purine derivative olomoucine-or roscovitine-related Cdk inhibitors by combinatorial chemistry and studied their e ects on cell cycle distribution and their ability to induce apoptosis. One of these inhibitors designated 209 induced apoptosis without a ecting overall cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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“…13,16,22,32,33 In this study new aspects of the structure-activity relationship became apparent, including correlation with effect on cell proliferation.…”

Section: Structure-activity Relationshipmentioning

confidence: 99%

Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases

et al. 2002

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In this study, analogues of olomoucine, a previously described plant cytokinin analogue with cyclin-dependent kinase (CDK) inhibitory activity, were investigated for effect on CDK1 and CDK2 and for effect on cell proliferation. Eight new compounds exhibit stronger inhibitory activity on CDK1 and CDK2 and on cell proliferation than olomoucine. Some active compounds showed low inhibition of proliferation of normal myeloid growth. Improvement of inhibitory activity of known compounds with a C6-benzylamino group was brought about by substitution with one hydroxyl. Also, new C2 substituents associated with inhibitory activity on CDK and on cell proliferation are described. There was a significant correlation between effect on CDK and antiproliferative effect on the KG1 and Molt3 cell lines and on primary human lymphocytes, strongly suggesting that at least part of the antiproliferative effect of cytokinin analogues was due to inhibition of CDK activity. Cytokinin analogues induced apoptosis in a time-and concentration-dependent manner and changes in cell cycle distribution. The antiproliferative and pro-apoptotic effects of plant cytokinin analogues suggest that they are a new class of cytostatic agents and that they may find an application in the chemotherapy of cancer. Leukemia (2002) 16, 299-305.

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“…We report here that indirubins are very potent inhibitors (IC 50 values in the 5-50 nM range) of glycogen synthase kinase-3␤ (GSK-3␤). This kinase is an essential element of the WNT signaling pathway (29).…”

mentioning

confidence: 99%

“…The kinase selectivity study showed that indirubins have a strong affinity for CDKs (IC 50 values in the range of 50 -100 nM) (25). Nevertheless, they are not totally devoid of activity toward a few kinases (IC 50 values in the 1-10 M range) (25). This rather loose selectivity, when compared with the high specificity of purine inhibitors of CDKs, led us to continue to investigate the selectivity of indirubins as kinase inhibitors.…”

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confidence: 99%

Indirubins Inhibit Glycogen Synthase Kinase-3β and CDK5/P25, Two Protein Kinases Involved in Abnormal Tau Phosphorylation in Alzheimer's Disease

Leclerc¹,

Garnier²,

Hoessel³

et al. 2001

Journal of Biological Chemistry

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The bis-indole indirubin is an active ingredient of Danggui Longhui Wan, a traditional Chinese medicine recipe used in the treatment of chronic diseases such as leukemias. The antitumoral properties of indirubin appear to correlate with their antimitotic effects. Indirubins were recently described as potent (IC 50 : 50 -100 nM) inhibitors of cyclin-dependent kinases (CDKs). We report here that indirubins are also powerful inhibitors (IC 50 : 5-50 nM) of an evolutionarily related kinase, glycogen synthase kinase-3 ␤ (GSK-3 ␤). Testing of a series of indoles and bis-indoles against GSK-3 ␤, CDK1/cyclin B, and CDK5/p25 shows that only indirubins inhibit these kinases. The structure-activity relationship study also suggests that indirubins bind to GSK-3␤'s ATP binding pocket in a way similar to their binding to CDKs, the details of which were recently revealed by crystallographic analysis. GSK-3 ␤, along with CDK5, is responsible for most of the abnormal hyperphosphorylation of the microtubule-binding protein tau observed in Alzheimer's disease. Indirubin-3-monoxime inhibits tau phosphorylation in vitro and in vivo at Alzheimer's diseasespecific sites. Indirubins may thus have important implications in the study and treatment of neurodegenerative disorders. Indirubin-3-monoxime also inhibits the in vivo phosphorylation of DARPP-32 by CDK5 on Thr-75, thereby mimicking one of the effects of dopamine in the striatum. Finally, we show that many, but not all, reported CDK inhibitors are powerful inhibitors of GSK-3␤. To which extent these GSK-3␤ effects of CDK inhibitors actually contribute to their antimitotic and antitumoral properties remains to be determined. Indirubins constitute the first family of low nanomolar inhibitors of GSK-3 ␤ to be described.

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Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors

Cited by 273 publications

References 18 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

Antiproliferative effect of plant cytokinin analogues with an inhibitory activity on cyclin-dependent kinases

Indirubins Inhibit Glycogen Synthase Kinase-3β and CDK5/P25, Two Protein Kinases Involved in Abnormal Tau Phosphorylation in Alzheimer's Disease

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