Ibition cellular Ren goals of treatment. That all of these new in vivo model systems h Will be higher than in animal models of xenograft or syngeneic h Ufigsten BI6727 Volasertib used remains to be seen. The importance of CDKs in the regulation of cell cycle, has its interaction with oncogenes and tumor suppressor genes and their h Ufigen deregulation in human tumors, an active search for agents to St Ments found their function Promoted. Produced a variety of low molecular weight selective inhibitors against the binding sites of ATP CDK1, CDK2 and CDK4 directed. Because of its control points G1/DNA the synthesis intact, normal cells are shown to be blocked by inhibitors of CDK reversibly in either G1 or G2 phase of the transition / mitosis.
In transformed cells, these checkpoints Either absent or defective cell apoptosis in vitro, a function Dependence of the target and the presence of tumor-suppressor. In addition, some of these inhibitors show some efficacy in vivo at moderate doses well tolerated Possible and provides a strong rationale for the development of new cell cycle antagonists for cancer therapy. The development of normal cells into cancer cells by the loss of fidelity mechanisms that replicate repair and disconnect the genome facilitated. These are Haupts Chlich by the CDK, the regulated contr To the checkpoints And repair mechanisms. After controlling the activation of mitogenic signaling, the cells through the cell cycle phases in strict POSE where the G1 phase separates the M and S phases.
Cdk-specific function in different phases of the cell cycle: D CDK4/cyclin Cdk6/CycD and are responsible for the progression through the G1 phase, Cdk2/CycE for the progression from G1 to S is required, is necessary for Cdk2/CycA by S , w during Cdk1/CycB for G2 / M. These CDK complexes are ben cyc CONFIRMS in turn by small inhibitory proteins, regulated so-called endogenous CDK inhibitors. INK4 family, which lt p16INK4a, p15INK4b, and p18INK4c p19INK4d contains Inhibits specifically Cdk4/CycD, w To bind while family members INK2 as p21WAF1, p27KIP1 and p57KIP2, and inhibit the activity t of Cdk2/CycE, Cdk2 / CycA, Cdk1/CycB, and less efficient Cdk4/CycD. The INK4 proteins, especially p16, block the Kinaseaktivit t Cdk4/CycD that in turn phosphorylates the retinoblastoma protein, causing it not in a G1 arrest. Contain up to 70% of tumor cells from various types of tumors Ver changes In the p16 locus.
The loss of p16 function leads to activation of the nitrogen with the carbonyl group of L83 Cdk4/CycDanilino, w While the amino group in ATP N6 E81 have a hydrogen atom to the carbonyl skeleton. Although CGP 60 474 is a potent inhibitor with a favorable selectivity spectrum of t, there were other unfavorable features, which prohibits its further development. Therefore, optimizing the purine derivative olomoucine, another promising structure with a reasonable selectivity of t for CDK2 and CDK1. However, lacking the power of olomoucine, the drug-Cdk inhibitor, as an interesting molecule to convert. The improvement in performance for Olomoucines was following a different construction on Ver published shall three-dimensional structures of CDK2 complexes. As the purine ring o