Synthesis, Structure−Activity Relationship, and Biological Studies of Indolocarbazoles as Potent Cyclin D1-CDK4 Inhibitors

Zhu, Guoxin; Conner, Scott E.; Zhou, Xun; Shih, Chuan; Li, Tiechao; Anderson, Bryan D.; Brooks, Harold B.; Campbell, Robert M.; Considine, Eileen L.; Dempsey, Jack; Faul, Margaret M.; Ogg, Cathy; Patel, Bharvin; Schultz, Richard M.; Spencer, Charles D.; Teicher, Beverly A.; Watkins, Scott A.

doi:10.1021/jm0256169

Cited by 98 publications

(67 citation statements)

References 31 publications

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“…Human melanoma cell lines 624Mel, A101D, and A375 harbor heterozygous BRAF T1799A mutation and loss of wild-type p16 (Rotolo et al, 2005). The cells are treated, alone or in combination, with MEK inhibitor PD98059 (Waters et al, 1995) and CDK4 inhibitor 219476 (Zhu et al, 2003). As anticipated, ERK phosphorylation is reduced in cells treated with PD98059 and PD98059 plus 219476 (Fig.…”

Section: Inhibition Of Mek and Cdk4 In Melanoma Cellssupporting

confidence: 54%

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Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Dong¹,

Chet²

2011

Treatment of Metastatic Melanoma

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Section: Inhibition Of Mek and Cdk4 In Melanoma Cellssupporting

confidence: 54%

“…10C). PD98059 and 219476 inhibit tumor cell growth in a dose dependent manner (Krasilnikov et al, 2003;Zhu et al, 2003). In order to make it possible to monitor the additional therapeutic www.intechopen.com (Li et al, 2010a).…”

Section: Inhibition Of Mek and Cdk4 In Melanoma Cellsmentioning

confidence: 99%

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Dong¹,

Chet²

2011

Treatment of Metastatic Melanoma

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“…CDK2 Inhibitor III and CDK4 inhibitor have been previously described (Bhattacharjee et al, 2001;Zhu et al, 2003). Roscovitine, CDK2 Inhibitor III and CDK4 inhibitor were purchased from Calbiochem (Darmstadt, Germany) and dissolved in DMSO.…”

Section: Drug Treatments and Gene Transfermentioning

confidence: 99%

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

2007

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Thymidylate synthase (TS) is the enzyme that catalyses the last step in de novo thymidylate synthesis. It is of interest clinically because it is an effective target for drugs such as 5-fluorouracil, often used in combination therapy. Despite a number of earlier reports indicating that TS is a cell cycle-dependent enzyme, this remains equivocal. Here, we show that in HCT116 cells synchronised by serum starvation, there is a clear dissociation between the expression of cyclin E (a well-characterised cell-cycle protein) and TS. Although both cyclin E and TS mRNA and protein increased during G 1 , TS upregulation was delayed. Moreover, TS levels did not decrease following S-phase completion while cyclin E decreased sharply. Similarly, clear differences were seen between cyclin E and TS as asynchronously growing HCT116 cells were growth-inhibited by low-serum treatment. In contrast to previous reports using rodent cells, adenovirus-mediated over-expression of E2F1 and cyclin E in three human cell lines had no effect on TS. Cell-cycle progression was blocked by treatment of cells with pharmacological inhibitors of CDK2 and CDK4 and by ectopic expression of p16INK4A. Whereas CDK2 inhibition had no effect on TS levels, inhibition of CDK4 was associated with decreased TS protein levels. These results provide the first evidence that drugs targeting CDK4 may be useful with anti-TS drugs as combination therapy for cancer.

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“…A variety of chemical classes, which include purine analogues (21 -25), pyrimidine analogues (26)(27)(28), indenopyrazoles (29,30), pyridopyrimidines (31)(32)(33), pyrazolopyridines (34,35), indolocarbazoles (36), pyrrolocarbazoles (37,38), oxindoles (39,40), and aminothiozoles (41) have been developed as Cdk inhibitors. Several compounds that inhibit Cdk activity are currently in clinical trials, including flavopiridol, R-roscovitine (CYC-202), UCN-01 (7-hydroxystaurosporine), and BMS-387032 either as single agents or in combination.…”

Section: Introductionmentioning

confidence: 99%

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

Joshi

Rathos

Joshi

et al. 2007

Molecular Cancer Therapeutics

117

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Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC 50 below 250 nmol/L. In this report, we have described the properties of one of the best compound,

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Synthesis, Structure−Activity Relationship, and Biological Studies of Indolocarbazoles as Potent Cyclin D1-CDK4 Inhibitors

Cited by 98 publications

References 31 publications

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Simultaneous Knockdown of Mutant BRAF and Expression of INK4A in Melanoma Cells Leads to Potent Growth Inhibition and Apoptosis

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00

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