title: Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response.
abstract: Palbociclib is a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor approved for breast cancer that is estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative. We profiled palbociclib in cells either sensitive or resistant to the drug using an ATP/ADP probe-based chemoproteomics platform. Palbociclib only engaged CDK4 or CDK6 in sensitive cells. In resistant cells, no inhibition of CDK4 or CDK6 was observed, although the off-target profiles were similar in both cell types. Prolonged incubation of sensitive cells with the compound (24 h) resulted in the downregulation of additional kinases, including kinases critical for cell cycle progression. This downregulation is consistent with cell cycle arrest caused by palbociclib treatment. Both the direct and indirect targets were also observed in a human tumor xenograft study using the COLO-205 cell line in which phosphorylation of the retinoblastoma protein was tracked as the pharmacodyanamic marker. Together, these results suggest that this probe-based approach could be an important strategy toward predicting patient responsiveness to palbociclib.
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Tyzoon K
authors: TK
authors: Nomanbhoy
authors: Agilux Laboratories , Three Biotech, One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors: Geeta
authors: G
authors: Sharma
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Heidi
authors: H
authors: Brown
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Jiangyue
authors: J
authors: Wu
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Arwin
authors: A
authors: Aban
authors: Agilux Laboratories , Three Biotech, One Innovation Drive, Worcester, Massachusetts 01605, United States.
authors: Subha
authors: S
authors: Vogeti
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Senait
authors: S
authors: Alemayehu
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Maria
authors: M
authors: Sykes
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: Jonathan S
authors: JS
authors: Rosenblum
authors: ActivX Biosciences , 11025 N. Torrey Pines Road, Suite 120, La Jolla, California 92037, United States.
authors: John W
authors: JW
authors: Kozarich
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib