Abstract
Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported.
Highlights
In both human and mouse models of melanoma, activation of the CDK4 pathway potently cooperates with mutant BRAF or NRAS in transformation of melanocytes and RAS/RAF/MEK/ERK pathway is dysregulated in 65% to 90% of metastatic melanoma, further enhancing CDK4 pathway signaling through increasing cyclin D1 expression [175,244]
AT7519 is a pyrazole derivative and multi CDK inhibitor, which has proven efficient towards several human cancer cell lines, which is administered to patients with advanced solid tumours or refractory non-Hodgkin’s lymphoma, and which is currently in phase 2 trials for multiple myeloma, chronic lymphocytic leukemia (CLL) and MCL [349,350,351,352,415] NU6140 [320], NU2058 and NU6027 [316,317] are second generation purines which inhibit CDKs more potently through formation of additional hydrogen bonds with CDK2
A peptide bearing the 84–103 (DAAREGFLATLVVHRAGAR) sequence of p16INK4a that interacts with CDK4 and CDK6 was found to inhibit phosphorylation of RB1 by CDK4/cyclin D1 in vitro, and block cell cycle progression when fused to Penetratin or TAT, in several cancer cell lines but not in an RB1-negative cell line [374,377] (Figure 6A,B)
Summary
Cyclin-dependent kinases [CDKs] were first identified independently in starfish, Xenopus and yeast and cloned in the 1970s–1980s as gene products involved in regulation of the cell division cycle [1,2,3,4,5,6]. The first CDK/Cyclin complexes to be characterized were bona fide regulators of cell growth and division, involved in the tight and timely control of cell cycle progression, through phosphorylation of substrates involved in DNA replication, chromatin condensation, assembly of the mitotic spindle and disassembly of the nuclear envelope. For this reason, they were thereafter considered as the “master regulators” of cell cycle progression, molecular engines that drive cell cycle transitions [10,11,12]. Wnt/β-catenin signaling trafficking of synaptic proteins and synapse remodeling spermatogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
