Open AccessJournal Article
Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts
David W. Fry,Patricia J. Harvey,Paul R. Keller,William Elliott,Maryanne Meade,Erin Trachet,Mudher Albassam,Xianxian Zheng,Wilbur R. Leopold,Nancy Pryer,Peter L. Toogood +10 more
TLDR
Results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.Abstract:
PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G1 arrest, with a concomitant reduction of phospho-Ser780/Ser795 on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.read more
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Palbociclib and Letrozole in Advanced Breast Cancer
Richard S. Finn,Miguel Martin,Hope S. Rugo,Stephen R. Jones,Seock-Ah Im,Karen A. Gelmon,Nadia Harbeck,Oleg Lipatov,Janice M. Walshe,Stacy L. Moulder,Eric Gauthier,Dongrui R. Lu,Sophia Randolph,Véronique Diéras,Dennis J. Slamon +14 more
TL;DR: Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with let rozole alone, although the rates of myelotoxic effects were higher with palbokiclib-letrozoles.
Journal ArticleDOI
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study
Richard S. Finn,John Crown,István Láng,Katalin Boér,Igor Bondarenko,Sergey O. Kulyk,Johannes Ettl,Ravindranath Patel,Tamás Pintér,Marcus Schmidt,Yaroslav Shparyk,Anu Thummala,Nataliya L. Voytko,Camilla Fowst,Xin Huang,Sindy T. Kim,Sophia Randolph,Dennis J. Slamon +17 more
TL;DR: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens as mentioned in this paper.
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Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Daniel Martinez Molina,Rozbeh Jafari,Marina Ignatushchenko,Takahiro Seki,E. Andreas Larsson,Chen Dan,Lekshmy Sreekumar,Yihai Cao,Yihai Cao,Pär Nordlund,Pär Nordlund +10 more
TL;DR: This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins and validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues.
Journal ArticleDOI
The history and future of targeting cyclin-dependent kinases in cancer therapy
TL;DR: How CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity is discussed.
Journal ArticleDOI
Melanoma biology and new targeted therapy
TL;DR: The incidence of melanoma is rising steadily in western populations — the number of cases worldwide has doubled in the past 20 years — and these advances are being exploited to provide targeted drugs and new therapeutic approaches.
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