Clinical anticancer drug development: targeting the cyclin-dependent kinases

Benson, Charlotte; Kaye, Stanley B.; Workman, Paul; Garrett, Michelle D.; Walton, Mike I.; Bono, Johann S. de

doi:10.1038/sj.bjc.6602229

Cited by 88 publications

(57 citation statements)

References 36 publications

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“…The pathogenesis of this possible alteration in renal blood flow remains unexplained. It has been proposed that binding of seliciclib to unrelated targets such as adenosine receptors, which regulate renal blood flow, could explain these findings, but this has not been confirmed to date (Benson et al, 2005). The reversibility of the renal dysfunction and absence of changes in urinary retinol-binding protein do, however, suggest that this was not related to clinically significant tubular damage.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

et al. 2006

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Seliciclib (CYC202; R-roscovitine) is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7 and 9 to enter clinical trial. Preclinical studies showed antitumour activity in a broad range of human tumour xenografts. A phase I trial was performed with a 7-day b.i.d. p.o. schedule. Twenty-one patients (median age 62 years, range: 39 -73 years) were treated with doses of 100, 200 and 800 b.i.d. Dose-limiting toxicities were seen at 800 mg b.i.d.; grade 3 fatigue, grade 3 skin rash, grade 3 hyponatraemia and grade 4 hypokalaemia. Other toxicities included reversible raised creatinine (grade 2), reversible grade 3 abnormal liver function and grade 2 emesis. An 800 mg portion was investigated further in 12 patients, three of whom had MAG3 renograms. One patient with a rapid increase in creatinine on day 3 had a reversible fall in renal perfusion, with full recovery by day 14, and no changes suggestive of renal tubular damage. Further dose escalation was precluded by hypokalaemia. Seliciclib reached peak plasma concentrations between 1 and 4 h and elimination half-life was 2 -5 h. Inhibition of retinoblastoma protein phosphorylation was not demonstrated in peripheral blood mononuclear cells. No objective tumour responses were noted, but disease stabilisation was recorded in eight patients; this lasted for a total of six courses (18 weeks) in a patient with ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days

et al. 2006

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“…Cyclin D1 overexpression, for example, is found in leukemia, lymphomas, and multiple myeloma, as well as in many solid tumors (4). Cyclin E and A overexpression is reported in 50% of breast and lung cancer, whereas decreased levels of the CDKIs such as p27 predict poor prognosis in breast, prostate, colon, gastric, lung, and esophageal cancer (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Dual Targeting of CDK and Tropomyosin Receptor Kinase Families by the Oral Inhibitor PHA-848125, an Agent with Broad-Spectrum Antitumor Efficacy

Albanese

Alzani

Amboldi

et al. 2010

Molecular Cancer Therapeutics

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Altered expression and activity of cyclin-dependent kinase (CDK) and tropomyosin receptor kinase (TRK) families are observed in a wide variety of tumors. In those malignancies with aberrant CDK activation, the retinoblastoma protein (pRb) pathway is deregulated, leading to uncontrolled cell proliferation. Constitutive activation of TRKs is instead linked to cancer cell survival and dissemination. Here, we show that the novel small-molecule PHA-848125, a potent dual inhibitor of CDKs and TRKs, possesses significant antitumor activity. The compound inhibits cell proliferation of a wide panel of tumoral cell lines with submicromolar IC 50 . PHA-848125-treated cells show cell cycle arrest in G 1 and reduced DNA synthesis, accompanied by inhibition of pRb phosphorylation and modulation of other CDK-dependent markers. The compound additionally inhibits phosphorylation of TRKA and its substrates in cells, which functionally express this receptor. Following oral administration, PHA-848125 has significant antitumor activity in various human xenografts and carcinogen-induced tumors as well as in disseminated primary leukemia models, with plasma concentrations in rodents in the same range as those found active in inhibiting cancer cell proliferation. Mechanism of action was also confirmed in vivo as assessed in tumor biopsies from treated mice. These results show that the dual CDK-TRK inhibitor PHA-848125 has the potential for being a novel and efficacious targeted drug for cancer treatment. Mol Cancer Ther; 9(8); 2243-54. ©2010 AACR.

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“…Cdks are highly conserved serine/threonine kinases whose activation depends on formation of a heterodimeric complex with cyclins [17][18][19]. Thus, Cdks are a promising therapeutic target for cancer treatment [20]. ROSC is a novel Cdk inhibitor that induces cell cycle arrest and apoptosis through multiple intracellular targets in a variety of tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%