CDK 抑制剂在抗肿瘤领域的研发进展

细胞周期蛋白依赖性激酶（cyclin dependent kinase，CDK）为细胞周期调节的关键激酶，参与细胞增殖、转录、存活等生理过程。 CDK 在多种肿瘤中异常活化，是抗肿瘤药物研发的重要靶点之一。目前已有 1 个 CDK 抑制剂（palbociclib, CDK4/CDK6 抑制剂）被美国 食品药品监督管理局批准于 2015 年上市，数十个 CDK 抑制剂处于针对实体瘤和血液系统肿瘤的临床或临床前研究阶段。综述目前抗肿瘤 领域 CDK 抑制剂的研发现状、遇到的问题和可能的解决方案，并讨论其临床应用的可能。     

Emerging pathogenic role for cyclin dependent kinases in neurodegeneration

While the requirement of CDKs in cell cycle control is well established, the participation of CDK family members in other important biological processes are now beginning to be uncovered. Paramount in these newly defined roles is the surprising involvement of CDKs in neuronal development and death. These discoveries are somewhat of a paradox considering the terminally differentiated state of neurons. This brief perspective will focus on the role of CDKs in neuronal death and neurodegeneration. In this regard, we will primarily explore two (of potentially many) ways by which CDKs may enable neuronal death. The first involves the effects of ectopic activation of cell cycle related CDKs in a terminal post mitotic environment. The second explores how cdk5, a neuron specific cdk required for normal neuronal function, can be usurped to signal death.     

Emerging Pathogenic Role for Cyclin Dependent Kinases in Neurodegeneration

While the requirement of CDKs in cell cycle control is well established, the participation of CDK family members in other important biological processes are now beginning to be uncovered. Paramount in these newly defined roles is the surprising involvement of CDKs in neuronal development and death. These discoveries are somewhat of a paradox considering the terminally differentiated state of neurons. This brief perspective will focus on the role of CDKs in neuronal death and neurodegeneration. In this regard, we will primarily explore two (of potentially many) ways by which CDKs may enable neuronal death. The first involves the effects of ectopic activation of cell cycle related CDKs in a terminal post mitotic environment. The second explores how cdk5, a neuron specific cdk required for normal neuronal function, can be usurped to signal death.     

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G₁/S transition and for efforts to target Cdk2 therapeutically in human cancers.     

Why minimal is not optimal: Driving the mammalian cell cycle—and drug discovery—with a physiologic CDK control network

Progression through the eukaryotic cell division cycle is governed by the activity of cyclin-dependent kinases (CDKs). For a CDK to become active it must (1) bind a positive regulatory subunit (cyclin) and (2) be phosphorylated on its activation (T) loop. In metazoans, multiple CDK catalytic subunits, each with a distinct set of preferred cyclin partners, regulate the cell cycle, but it has been difficult to assign functions to individual CDKs in vivo. Biochemical analyses and experiments with dominant-negative alleles suggested that specific CDK/cyclin complexes regulate different events, but genetic loss of interphase CDKs (Cdk2, -4 and -6), alone or in combination, did not block proliferation of cells in culture. These knockout and knockdown studies suggested redundancy or plasticity built into the CDK network but did not address whether there was true redundancy in normal cells with a full complement of CDKs. Here, we discuss recent work that took a chemical-genetic approach to reveal that the activity of a genetically non-essential CDK, Cdk2, is required for cell proliferation when normal cyclin pairing is maintained. These results have implications for the systems-level organization of the cell cycle, for regulation of the restriction point and G?/S transition and for efforts to target Cdk2 therapeutically in human cancers.     

Selective inhibition of proteins regulating CDK/cyclin complexes: strategy against cancer—a review

Cancer prevention is a global priority, but history indicates that the journey towards achieving the goal is difficult. Various cyclin dependent kinase complexes (CDKs/cyclins) operate as major cell signaling components in all stages of cell cycle. CDK/cyclin protein complexes, regulating the cell cycle, are conserved during evolution. In cancer cells, cell division is uncontrolled and CDKs/cyclins become ‘check-points’ or targets. Keeping this in view the proteins cyclin C, cyclin D2, CDKN1C, and Growth Arrest and DNA Damage (GADD45α) which play a major role in regulating CDK/cyclin complexes and operate in the initial stages of cell cycle (G₀ phase–S phase), have been identified as promising targets. Targeting critical regulators of cell-cycle signaling components by applying modern computational techniques is projected to be a potential tool for future cancer research.     

Structures of P. falciparum PfPK5 test the CDK regulation paradigm and suggest mechanisms of small molecule inhibition

Plasmodium falciparum cell cycle regulators are promising targets for antimalarial drug design. We have determined the structure of PfPK5, the first structure of a P. falciparum protein kinase and the first of a cyclin-dependent kinase (CDK) not derived from humans. The fold and the mechanism of inactivation of monomeric CDKs are highly conserved across evolution. ATP-competitive CDK inhibitors have been developed as potential leads for cancer therapeutics. These studies have identified regions of the CDK active site that can be exploited to achieve significant gains in inhibitor potency and selectivity. We have cocrystallized PfPK5 with three inhibitors that target such regions. The sequence differences between PfPK5 and human CDKs within these inhibitor binding sites suggest that selective inhibition is an attainable goal. Such compounds will be useful tools for P. falciparum cell cycle studies, and will provide lead compounds for antimalarial drug development.     

Activation of the Cdc42p GTPase by cyclin-dependent protein kinases in budding yeast

Cyclin-dependent kinases (CDKs) trigger essential cell cycle processes including critical events in G1 phase that culminate in bud emergence, spindle pole body duplication, and DNA replication. Localized activation of the Rho-type GTPase Cdc42p is crucial for establishment of cell polarity during G1, but CDK targets that link the Cdc42p module with cell growth and cell cycle commitment have remained largely elusive. Here, we identify the GTPase-activating protein (GAP) Rga2p as an important substrate related to the cell polarity function of G1 CDKs. Overexpression of RGA2 in the absence of functional Pho85p or Cdc28p CDK complexes is toxic, due to an inability to polarize growth. Mutation of CDK consensus sites in Rga2p that are phosphorylated both in vivo and in vitro by Pho85p and Cdc28p CDKs results in a loss of G1 phase-specific phosphorylation. A failure to phosphorylate Rga2p leads to defects in localization and impaired polarized growth, in a manner dependent on Rga2p GAP function. Taken together, our data suggest that CDK-dependent phosphorylation restrains Rga2p activity to ensure appropriate activation of Cdc42p during cell polarity establishment. Inhibition of GAPs by CDK phosphorylation may be a general mechanism to promote proper G1-phase progression.     

CP110, a cell cycle-dependent CDK substrate,regulates centrosome duplication in human cells

Centrosome duplication and separation are linked inextricably to certain cell cycle events, in particular activation of cyclin-dependent kinases (CDKs). However, relatively few CDK targets driving these events have been uncovered. Here, we have performed a screen for CDK substrates and have isolated a target, CP110, which is phosphorylated by CDKs in vitro and in vivo. Human CP110 localizes to centrosomes. Its expression is strongly induced at the G1-to-S phase transition, coincident with the initiation of centrosome duplication. RNAi-mediated depletion of CP110 indicates that this protein plays an essential role in centrosome duplication. Long-term disruption of CP110 phosphorylation leads to unscheduled centrosome separation and overt polyploidy. Our data suggest that CP110 is a physiological centrosomal CDK target that promotes centrosome duplication, and its deregulation may contribute to genomic instability.