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Ref Type Journal Article
PMID (17121911)
Authors DePinto W, Chu XJ, Yin X, Smith M, Packman K, Goelzer P, Lovey A, Chen Y, Qian H, Hamid R, Xiang Q, Tovar C, Blain R, Nevins T, Higgins B, Luistro L, Kolinsky K, Felix B, Hussain S, Heimbrook D
Title In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.
Journal Molecular cancer therapeutics
Vol 5
Issue 11
Date 2006 Nov
URL
Abstract Text The cyclin-dependent protein kinases are key regulators of cell cycle progression. Aberrant expression or altered activity of distinct cyclin-dependent kinase (CDK) complexes results in escape of cells from cell cycle control, leading to unrestricted cell proliferation. CDK inhibitors have the potential to induce cell cycle arrest and apoptosis in cancer cells, and identifying small-molecule CDK inhibitors has been a major focus in cancer research. Several CDK inhibitors are entering the clinic, the most recent being selective CDK2 and CDK4 inhibitors. We have identified a diaminopyrimidine compound, R547, which is a potent and selective ATP-competitive CDK inhibitor. In cell-free assays, R547 effectively inhibited CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D1 (K(i) = 1-3 nmol/L) and was inactive (K(i) > 5,000 nmol/L) against a panel of >120 unrelated kinases. In vitro, R547 effectively inhibited the proliferation of tumor cell lines independent of multidrug resistant status, histologic type, retinoblastoma protein, or p53 status, with IC(50)s </= 0.60 mumol/L. The growth-inhibitory activity is characterized by a cell cycle block at G(1) and G(2) phases and induction of apoptosis. R547 reduced phosphorylation of the cellular retinoblastoma protein at specific CDK phosphorylation sites at the same concentrations that induced cell cycle arrest, suggesting a potential pharmacodynamic marker for clinical use. In vivo, R547 showed antitumor activity in all of the models tested to date, including six human tumor xenografts and an orthotopic syngeneic rat model. R547 was efficacious with daily oral dosing as well as with once weekly i.v. dosing in established human tumor models and at the targeted efficacious exposures inhibited phosphorylation of the retinoblastoma protein in the tumors. The selective kinase inhibition profile and the preclinical antitumor activity of R547 suggest that it may be promising for development for use in the treatment of solid tumors. R547 is currently being evaluated in phase I clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
R547 R547 12 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
R547 R-547|R 547|RO 4584820|RO4584820 CDK1 Inhibitor 13 CDK2 Inhibitor 21 CDK4 Inhibitor 14 R547 is a small molecule that selectively inhibits cyclin-dependent kinases, leading to cell cycle arrest and apoptosis in cancer cells (PMID: 17121911, PMID: 32123493).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RB1 wild-type TP53 mut breast carcinoma sensitive R547 Preclinical - Cell line xenograft Actionable In a preclinical study, R547 inhibited proliferation of breast carcinoma cell lines harboring mutant Tp53 and wild-type Rb1 in culture and reduced tumor growth in xenograft models (PMID: 17121911). 17121911
RB1 wild-type TP53 wild-type colon carcinoma sensitive R547 Preclinical - Cell line xenograft Actionable In a preclinical study, R547 inhibited proliferation of colon carcinoma cell lines harboring wild-type Tp53 and Rb1 in culture and reduced tumor growth in xenograft models (PMID: 17121911). 17121911
RB1 wild-type TP53 wild-type breast carcinoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of breast carcinoma cell lines harboring wild-type Tp53 and Rb1 (PMID: 17121911). 17121911
RB1 wild-type TP53 wild-type lung carcinoma sensitive R547 Preclinical - Cell line xenograft Actionable In a preclinical study, R547 inhibited proliferation of lung carcinoma cell lines harboring wild-type Tp53 and Rb1 in culture and reduced tumor growth in xenograft models (PMID: 17121911). 17121911
RB1 wild-type TP53 mut osteosarcoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of osteosarcoma cell lines harboring mutant Tp53 and wild-type Rb1 (PMID: 17121911). 17121911
RB1 wild-type TP53 mut colon carcinoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of colon carcinoma cell lines harboring mutant Tp53 and wild-type Rb1 (PMID: 17121911). 17121911
RB1 wild-type TP53 wild-type mantle cell lymphoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of mantle cell lymphoma cell lines harboring wild-type Tp53 and Rb1 (PMID: 17121911). 17121911
RB1 mut TP53 mut cervical cancer sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of cervical carcinoma cell lines harboring Tp53 and Rb1 mutations (PMID: 17121911). 17121911
RB1 wild-type TP53 mut mantle cell lymphoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of mantle cell lymphoma cell lines harboring mutant Tp53 and wild-type Rb1 (PMID: 17121911). 17121911
RB1 mut TP53 mut prostate carcinoma sensitive R547 Preclinical - Cell line xenograft Actionable In a preclinical study, R547 inhibited proliferation of prostate carcinoma cell lines harboring Tp53 and Rb1 mutations in culture and reduced tumor growth in xenograft models (PMID: 17121911). 17121911
RB1 wild-type TP53 wild-type melanoma sensitive R547 Preclinical - Cell line xenograft Actionable In a preclinical study, R547 inhibited proliferation of melanoma cell lines harboring wild-type Tp53 and Rb1 in culture and reduced tumor growth in xenograft models (PMID: 17121911). 17121911
RB1 mut TP53 mut breast carcinoma sensitive R547 Preclinical Actionable In a preclinical study, R547 inhibited proliferation of breast carcinoma cell lines harboring TP53 and RB1 mutations in culture (PMID: 17121911). 17121911