细胞周期靶向的药物筛选.ppt

Cell-cycle-targeting Drugs,Sun Hong Pharm-Tox Team,Introduction,Many existing cancer chemotherapies interfere with DNA replication and formation of the mitotic spindle, that is, the processes central to the cell cycle. Alternative strategies aimed at targeting cell-cycle components that are specifically deregulated in tumour cells are now being explored. Several groups of protein kinases associated with aberrant tumour cell-cycle checkpoints are used as targets for the discovery of small-molecule inhibitor. The first of these compounds are now being evaluated in the clinic.,Conventional cell-cycle-related strategies in oncology,DNA-damaging agents Antimetabolites Topoisomerase inhibitors Agents that disrupt the microtubules of the mitotic spindle,New cell-cycle-related strategies in oncology,Normal cells rely on mitogenic stimulation to enter the cycle. Cancer cells enter and stay in cycle permanently, leading to the unchecked growth of tumours. Furthermore, DNA and spindle checkpoints are also frequently overridden in transformed cells. Reinstating cell-cycle control via pharmacological targeting of deregulated components of the checkpoint pathways should be a viable strategy in anticancer therapy.,The mammalian cell cycle,Cell-cycle-targeting Drugs,Drugs targeting G1/S G2 checkpoint abrogators Mitosis and its drug targets,Targeting G1/S,The mainstay of cell-cycle-targeted therapeutic strategies,until recently, has been pharmacological reinstatement of G1/S checks in tumour cells. Early approaches were based on gene therapy with CDK-directed tumour-suppressor proteins. More recently, these indirect approaches have been supplanted by small-molecule agents, especially CDK inhibitors.,G2 checkpoint abrogators,The main purpose of the G2 checkpoint is to allow time for the cell to repair damaged DNA before mitotic entry. As a consequence of G1 checkpoint defects, tumour cells appear to depend on the G2 checkpoint more than normally proliferating cells. Abrogation of this checkpoint should, therefore, deny tumour cells the opportunity to repair damaged DNA and should sensitise them towards DNA damaging chemotherapy.,Kinase inhibitors with G2-checkpoint abrogating properties,Methylxanthine derivatives caffeine Pentoxyfilline Indolocarbazoles such as UCN-01 and SB-218078,Mitosis and its drug targets,Direct inhibition of the mitotic spindle with agents such as paclitaxel, docetaxel and vinblastine has been successful therapeutically. However, toxicity, drug resistance, complex galenic formulations and poor bioavailability limit the clinical use of spindle poisons in cancer therapy.,Alternative antimitotic strategies,Kinesins PLKs Aurora kinases,Kinesins,Kinesins constitute a fairly diverse family of microtubule motor proteins that are required for bipolar spindle formation. The first small molecule monastrol reversibly and selectively inhibits kinesin-like spindle protein by blocking the ATPase activity of KSP. As KSP is selectively overexpressed in malignant cells and functions exclusively in mitosis, KSP inhibitors might be useful as cancer drugs.,PLKs,The polo-like kinases (PLKs) have recently emerged as important cell-cycle regulators. At the G2M transition, PLKs appear to oppose CHK activity by activating CDC25C, thereby activating CDK1cyclinB. It has already been demonstrated that depletion of PLKs in tumour cells induces apoptosis, although the development of pharmacological PLK inhibitors is still at an early stage.,Aurora kinases,Aurora A kinase and Aurora B kinase have important roles in regulating mitotic progression, especially at the level of centrosome maturation and chromosome segregation. Various genetic studies demonstrate that both Aurora A and B kinases are essential for cell prol