Cyclin-Dependent Kinases

Research into the cyclin-dependent kinases and their inhibitors is finally coming into the forefront of clinical research in cancer. Targeted therapies such as BRAF inhibitors have led the
way in improving treatment outcomes in advanced melanoma. Based on detailed genomic knowledge of melanoma it is now time to extend targeted therapies beyond BRAF to fulfill the
vision of precision medicine. The p16INK4A-cyclin D-CDK4/6-retinoblastoma protein pathway (RB pathway) is dysregulated in more than 90% of melanomas and interacts biochemically
and genetically with the RAS/RAF/MEK/ERK pathway. Recognizing and understanding these processes that drive melanomagenesis is essential to rationally develop new therapies. This paper reviews the mechanisms, background and progress of small molecule CDK4 inhibitors in the management of melanoma.

Ineffectiveness of conventional chemotherapeutic drugs and appearance of several side effects such as hair loss and anemia, nausea, vomiting, diarrhea, infections, fatigue and destruction of the immune system, due to inability to discriminate normal cells and cancerous cells, have led to development of new anti proliferative drugs with less side effect and more efficacy .Cell cycle and cell regulation play significant role in drug discovery as they  provide new opportunities for discovery of new drug target for treatment of cancers. CDKs are introduced as significant target for anticancer drugs as they are directly and indirectly involved in cell cycle events such as progression, transcription and DNA repair, so development of Cdk inhibitors become goal of many drug discovery companies and researchers, for treatment of cancers.  In this paper  we focused on Cdks , their regulatory role in cell cycle and  their prominent characteristics as valid target for drug discovery . Finally, we have reviewed 14 upcoming anticancer candidates whose target is CDKs .These anticancer drugs are such as Flavopiridol, Roscovitine, Dinaciclib, SNS032, AT7519, PD0332991, RGB-286638, P276-00, BAY-1000394, TG02/SG1317, EM-1421. PHA-848125. LEE-011 and LY2835219 which are currently under investigation for treatment of cancer. We hope this paper gives informative background for understanding  importance of Cdks as effective targets for cancer therapy with high effective results and minimum  side effect .

Background: Cancer refers to a group of some of the worldwide most diagnosed and deadliest pathophysiological conditions that conquered researchers' attention for decades and yet begs for more questions for a full comprehension of its complex cellular and molecular pathology. Main body: The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows. Conclusions: This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models.

There is mounting evidence to suggest that the synthesis of pre-mRNA transcripts and their subsequent splicing are coordinated events. Previous studies have implicated the mammalian spliceosomal U2 snRNP as having a novel role in stimulating transcriptional elongation in vitro through interactions with the elongation factors P-TEFb and Tat-SF1; however, the mechanism remains unknown [1]. These factors are conserved in Saccharomyces cerevisiae, a fact that suggests that a similar interaction may occur in yeast to stimulate transcriptional elongation in vivo. To address this possibility we have looked for evidence of a role for the yeast Tat-SF1 homolog, Cus2, and the U2 snRNA in regulating transcription. Specifically, we have performed a genetic analysis to look for functional interactions between Cus2 or U2 snRNA and the P-TEFb yeast homologs, the Bur1/2 and Ctk1/2/3 complexes. In addition, we have analyzed Cus2-deleted or -overexpressing cells and U2 snRNA mutant cells to determine if they show transcription-related phenotypes similar to those displayed by the P-TEFb homolog mutants. In no case have we been able to observe phenotypes consistent with a role for either spliceosomal factor in transcription elongation. Furthermore, we did not find evidence for physical interactions between the yeast U2 snRNP factors and the P-TEFb homologs. These results suggest that in vivo, S. cerevisiae do not exhibit functional or physical interactions similar to those exhibited by their mammalian counterparts in vitro. The significance of the difference between our in vivo findings and the previously published in vitro results remains unclear; however, we discuss the potential importance of other factors, including viral proteins, in mediating the mammalian interactions.

In the sheep, there is a rapid increase in fetal adrenal growth and steroidogenesis during the last 10–15 days gestation. Recently, we have shown that infusion of POMC 1–77 increases fetal adrenal growth but does not significantly alter fetal plasma cortisol concentrations. Phosphorylation and inactivation of the pRB protein, which is required for progression into the DNA synthetic phase of the cell-cycle is conducted by a holoenzyme, for which cyclin D1 gene encodes the rate-limiting regulatory subunit. To further elucidate the mechanisms by which POMC 1–77 regulates adrenal growth, we therefore examined adrenal expression of the rate-limiting cell cycle protein, cyclin D1, from fetuses infused for 48 hr with POMC 1–77 (n=6), POMC 1–49 or Saline (n=6). There was no significant difference in the adrenal expression of cyclin D1 mRNA levels between POMC 1–77, 1–49 and saline infused fetuses. There was no significant correlation between cyclin D1 (4.0 Kb) and adrenal weight. In summary, these data do not demonstrate that the rate-limiting cell cycle protein, cyclin D1, is activated to stimulate adrenal growth following infusion of POMC 1–77 in the fetal sheep in late gestation.