Apr 1, 2004 · Here, we report a comprehensive study of known selective inhibitors of CDK4 and describe the structural basis for their preferential inhibition over CDK2. We have constructed a homology model of CDK4 and used this model in order to dock structures of published inhibitors.

Jun 6, 2014 · CDK4 was characterized both as an inactive, nonphosphorylated monomer (CDK4) and as the fully activated binary complex (CDK4/cyclin D3 phosphorylated on Thr172, pCDK4/D).

Three dual CDK4/6 inhibitors have been approved for the breast cancer treatment that, in combination with the endocrine therapy, dramatically improved the survival outcomes both in first and later line settings.

Jan 10, 2020 · We aggregate these data with subsaturation mutagenesis data and use it to develop, test and validate a framework to prospectively identify residues that mediate kinase activity and drug resistance...

This review discusses the role that CDK4 plays in cell cycle control, normal development and tumorigenesis as well as the current status and utility of approved small molecule CDK4/6 inhibitors that are currently being used as cancer therapeutics. Keywords: CDK4/6, cancer, cell cycle, targeted therapy, checkpoint inhibitor

Dec 1, 2017 · In this study, we aim to find new ATP competitive leads of CDK4 by the combined 3D-QSAR pharmacophore mapping and molecular docking approach. The binding mode analysis of docked complexes comprising leads and known inhibitors towards selective CDK4 inhibition is focused, and an early ADME profiling to prioritize lead molecules is considered. 2.

May 14, 2024 · CDK4, paired with cyclin-D, operates in the long G1 phase, while CDK2 with cyclin-E, manages the brief G1-to-S transition, enabling DNA replication. Aberrant CDK signaling leads to uncontrolled cell proliferation, which is a hallmark of cancer.

This knowledge was applied to the design of compounds in the otherwise CDK2-selective 2-anilino-4- (thiazol-5-yl)pyrimidine pharmacophore that are potent and highly selective ATP antagonists of CDK4/cyclin D1. The findings of this study also have significant implications in the design of CDK4 mimic structures based on CDK2.

Further key features, including high dock score value, good predicted activity, scaffold diversity, and the acceptable ADME profile of leads, provide a great opportunity for the development of highly potent and selective ATP competitive inhibitors of CDK4.

May 14, 2024 · Key features of cyclin-D/CDK4/6: ATP binding site dynamics: CDK4’s active state has a more expansive ATP binding site characterized by a highly flexible G-loop and varying distance between hydrophobic residues that sandwich ATP.