TY - JOUR
T1 - In vitro and in vivo activity of R547
T2 - A potent selective cyclin-dependent kinase inhibitor currently in phase I clinical trials
AU - DePinto, Wanda
AU - Chu, Xin Jie
AU - Smith, Melissa
AU - Packman, Kathryn
AU - Goelzer, Petra
AU - Lovey, Allen
AU - Chen, Yingsi
AU - Qian, Hong
AU - Hamid, Rachid
AU - Xiang, Qing
AU - Tovar, Christian
AU - Blain, Roger
AU - Nevins, Tom
AU - Higgins, Brian
AU - Luistro, Leopoldo
AU - Kolinsky, Kenneth
AU - Felix, Bernardo
AU - Hussain, Sazzard
AU - Heimbrook, David
PY - 2006/11
Y1 - 2006/11
N2 - The cyclin-dependent protien 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 (Ki = 1-3 nmol/L) and was inactive (Ki > 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 IC50s ≤ 0.60 μmol/L. The growth-inhibitory activity is characterized by a cell cycle block at G1 and G2 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.
AB - The cyclin-dependent protien 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 (Ki = 1-3 nmol/L) and was inactive (Ki > 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 IC50s ≤ 0.60 μmol/L. The growth-inhibitory activity is characterized by a cell cycle block at G1 and G2 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.
UR - http://www.scopus.com/inward/record.url?scp=33750469601&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-06-0355
DO - 10.1158/1535-7163.MCT-06-0355
M3 - Article
C2 - 17121911
AN - SCOPUS:33750469601
SN - 1535-7163
VL - 5
SP - 2644
EP - 2658
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 11
ER -