In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer. 相似文献
A number of selective inhibitors of the CDK4/cyclin D1 complex have been reported recently. Due to the absence of an experimental CDK4 structure, the ligand and protein determinants contributing to CDK4 selectivity are poorly understood at present. Here, we report the use of computational methods to elucidate the characteristics of selectivity and to derive the structural basis for specific, high-affinity binding of inhibitors to the CDK4 active site. From these data, the hypothesis emerged that appropriate incorporation of an ionizable function into a CDK2 inhibitor results in more favorable binding to CDK4. This knowledge was applied to the design of compounds in the otherwise CDK2-selective 2-anilino-4-(thiazol-5-yl)pyrimidine pharmacophore that are potent and highly selective ATP antagonists of CDK4/cyclin D1. The findings of this study also have significant implications in the design of CDK4 mimic structures based on CDK2. 相似文献
Asperchalasine A ( 1 ), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B–D ( 2 – 4 ), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single‐crystal X‐ray diffraction techniques. Compound 1 , which possesses an unprecedented 13‐oxatetracyclo[7.2.1.12,5.01,6]tridec‐8,12‐dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1 – 4 were described starting from the co‐isolated compounds 5 and 6 . More importantly, 1 induced significant G1‐phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells. 相似文献
Asperchalasine A ( 1 ), the first cytochalasan dimer featuring a unique decacyclic 5/6/11/5/5/6/5/11/6/5 ring system consisting of 20 chiral centers, was isolated from the culture broth of Aspergillus flavipes. Three biogenetically related intermediates, asperchalasines B–D ( 2 – 4 ), were also isolated. Their structures, including their absolute configurations, were elucidated using a combination of HRESIMS, NMR, ECD, molecular modeling, and single‐crystal X‐ray diffraction techniques. Compound 1 , which possesses an unprecedented 13‐oxatetracyclo[7.2.1.12,5.01,6]tridec‐8,12‐dione core structure, is the first example of a dimeric cytochalasan alkaloid. The biogenetic pathways of 1 – 4 were described starting from the co‐isolated compounds 5 and 6 . More importantly, 1 induced significant G1‐phase cell cycle arrest by selectively inhibiting cyclin A, CDK2 and CDK6 in cancerous, but not normal, cells, highlighting it as a potentially selective cell cycle regulator against cancer cells. 相似文献
Cyclin dependent kinases (CDKs) have recently raised considerable attention because of their central role in the regulation of cell cycle progression. A high incidence of genetic mutation of CDK substrates and deregulation of CDK modulators were found in a number of disease states, particularly in cancer. A novel series of unsymmetrical substituted indolocarbazoles were synthesized and their kinase inhibitory capability was evaluated in vitro. 6-Substituted indolocarbazoles were found to b… 相似文献
Summary Cyclin-dependent kinases (CDKs) play a key role in regulating the cell cycle. The cyclins, their activating agents, and endogenous CDK inhibitors are frequently mutated in human cancers, making CDKs interesting targets for cancer chemotherapy. Our aim is the discovery of selective CDK4/cyclin D1 inhibitors. An ATP-competitive pyrazolopyrimidinone CDK inhibitor was identified by HTS and docked into a CDK4 homology model. The resulting binding model was consistent with available SAR and was validated by a subsequent CDK2/inhibitor crystal structure. An iterative cycle of chemistry and modeling led to a 70-fold improvement in potency. Small substituent changes resulted in large CDK4/CDK2 selectivity changes. The modeling revealed that selectivity is largely due to hydrogen-bonded interactions with only two kinase residues. This demonstrates that small differences between enzymes can efficiently be exploited in the design of selective inhibitors. 相似文献
Cyclin-dependent kinases (CDKs) have become potential targets for treating various diseases, especially cancer. Compound iCDK9 is an excellent and selective CDK9 inhibitor, but its major limitation is the potential toxicity and poor understanding of the underlying mechanism. The PROTAC (proteolysis targeting chimera) degraders of bioactive molecules can significantly induce in vitro and in vivo degradation of their target protein with high selectivity and effectively reduce the dose-limiting toxicity of small molecule drugs. Therefore, we designed and synthesized the bifunctional PROTAC molecules of iCDK9, being used for identifying its previously unknown target and revealing the underlying pharmacological mechanism. The PROTAC bifunctional molecule CD-5 could selectively and significantly degrade CDK9 with low cell toxicity. Therefore, we selected CD-5 as a chemical prober in the SILAC quantitative proteomic analysis, which disclosed that CD-5 could enormously lessen the lysine acetyltransferase KAT6A. Furthermore, KAT6A degradation induced by CD-5 repressed the levels of H3K14Ac and H3K23Ac. Lastly, the streptavidin immunoprecipitation (IP) assay confirmed a direct interaction between KAT6A and iCDK9. Collectively, our results uncover that KAT6A is a potential non-kinase target of iCDK9. Notably, this study also demonstrates that the PROTAC-SILAC strategy is an alternative approach for cellular target identification of bioactive molecules. 相似文献
A series of RuII–arene complexes ( 1 – 6 ) of the general formula [(η6‐arene)Ru(L)Cl]PF6 (arene=benzene or p‐cymene; L=bidentate β‐carboline derivative, an indole alkaloid with potential cyclin‐dependent kinases (CDKs) inhibitory activities) is reported. All the complexes were fully characterized by classical analytical methods, and three were characterized by X‐ray crystallography. Hydrolytic studies show that β‐carboline ligands play a vital role in their aqueous behaviour. These complexes are highly active in vitro, with the most active complex 6 displaying a 3‐ to 12‐fold higher anticancer activity than cisplatin against several cancer cell lines. Interestingly, the complexes are able to overcome cross‐resistance to cisplatin, and show much lower cytotoxicity against normal cells. Complexes 1 – 6 may directly target CDK1, because they can block cells in the G2M phase, down‐regulate the expression of CDK1 and cyclin B1, and inhibit CDK1/cyclin B in vitro. Further mechanism studies show that the complexes can effectively induce apoptosis through mitochondrial‐related pathways and intracellular reactive oxygen species (ROS) elevation. 相似文献
An approach to spiropyrazole derivatives containing iminolactone and/or cyclic imide moiety starting from 1H‐pyrazole‐4‐acetic acid derivative is described. Hydrolysis of C‐cyanomethylated 1H‐pyrazole‐4‐acetic acid methyl ester ( 1 ), which was easily prepared from 1H‐pyrazole‐4‐acetic acid derivative by a C‐cyanomethylation, led to the C‐cyanomethylated 1H‐pyrazole‐4‐acetic acid ( 2 ). Compound 2 was reacted with ethanol in the presence of tin(IV) chloride in refluxing chloroform to give the key intermediate ethyl imidate ( 3 ). Sodium hydride‐assisted lactonization of 3 in N,N‐dimethylformamide afforded the spiropyrazole derivative containing iminolactone moiety ( 4 ). On the other hand, thermal treatment of 3 with sodium acetate in the absence of solvent caused another intramolecular cyclization to yield the spiropyrazole derivative containing cyclic imide moiety ( 6 ). 相似文献
Reverse‐selective membranes , through which bigger molecules selectively permeate, are attractive for developing chemical processes utilizing hydrogen because they can maintain the high partial pressure of hydrogen required for further downstream utilization. Although several of these chemical processes are operated above 473 K, membranes with outstanding reverse‐selective separation performance at these temperatures are still to be reported. M. Matsukata et al. propose a new adsorption‐based reverse‐selective membrane that utilizes a Na cation occluded in a zeolitic framework. The membrane developed in this work enables selective permeation and separation of bigger polar molecules, such as methanol and water, from hydrogen above 473 K. For more information, see their Full Paper on page 1070 ff.
Future spaceflight missions focused on life detection will carry with them new, state‐of‐the‐art instrumentation capable of highly selective and sensitive organic analysis. CE–LIF is an ideal candidate for such a mission due to its high separation efficiency and low LODs. One perceived risk of utilizing this technique on a future mission is the stability of the chemical reagents in the spaceflight environment. Here, we present an investigation of the thermal stability of the fluorescent dye (5‐carboxyfluorescein succinimidyl ester) used for amino acid analysis. The dye was stored at 4, 25, and 60°C for 1 month, 6 months, 1 year, and 2 years. When stored at 4°C for 2 years, 25°C for 6 months, or 60°C for 1 month there was no effect on CE‐LIF assay performance due to dye degradation. Beyond these time points, while the dye degradation begins to interfere with the analysis, it is still possible to perform the analysis and achieve the majority of amino acid biosignature science goals described in the science definition team report for the potential Europa Lander mission. This work indicates that thermal control of the dye at ≤4°C will be needed during transit on future spaceflight missions to maintain dye stability. 相似文献
CDK2 and CDK4 known promoter of cell cycling catalyze phosphorylation of RB protein. Enzyme specificity between two CDKs that work at a different cell cycle phase is not clearly understood. In order to define kinase properties of CDK2 and CDK4 in complex with cycline A or cycline D1 in relation to their respective role in cell cycling regulation, we examined enzymatic properties of both CDK4/cycline D1 and CDK2/cycline A in vitro. Association constant, Km for ATP in CDK4/cyclin D1 was found as 418 microM, a value unusually high whereas CDK2/cyclin A was 23 microM, a value close to most of other regulatory protein kinases. Turnover value for both CDK4/cyclin D1 and CDK2/cyclin A were estimated as 3.4 and 3.9 min(-1) respectively. Kinetic efficiency estimation indicates far over one order magnitude less efficiency for CDK4/cyclin D1 than the value of CDK2/cycline A (9.3 pM(-1) min(-1) and 170 pM(-1) min(-1) respectively). In addition, inhibition of cellular CDK4 caused increase of cellular levels of ATP, even though inhibition of CDK2 did not change it noticeably. These data suggest cellular CDK4/cyclin D1 activity is tightly associated with cellular ATP concentration. Also, analysis of phosphorylated serine/threonine sites on RB catalyzed by CDK4/cyclin D1 and CDK2/cyclin A showed significant differences in their preference of phosphorylation sites in RB C-terminal domain. Since RB is known to regulate various cellular proteins by binding and this binding is controlled by its phosphorylation, these data shown here clearly indicate significant difference in their biochemical properties between CDK4/cyclin D1 and CDK2/cyclin A affecting regulation of cellular RB function. 相似文献
We report lipase‐based nanomotors that are capable of enhanced Brownian motion over long periods of time in triglyceride solution and of degrading triglyceride droplets that mimic “blood lipids”. We achieved about 40 min of enhanced diffusion of lipase‐modified mesoporous silica nanoparticles (MSNPs) through a biocatalytic reaction between lipase and its corresponding water‐soluble oil substrate (triacetin) as fuel, which resulted in an enhanced diffusion coefficient (ca. 50 % increase) at low triacetin concentration (<10 mm ). Lipase not only serves as the power engine but also as a highly efficient cleaner for the triglyceride droplets (e.g., tributyrin) in PBS solution, which could yield potential biomedical applications, for example, for dealing with diseases related to the accumulation of triglycerides, or for environmental remediation, for example, for the degradation of oil spills. 相似文献
Amphiphilic molecules have received wide attention as they possess both hydrophobic and hydrophilic properties, and can form diverse nanostructures in selective solvents. Herein, we report an asymmetric amphiphilic zwitterionic perylene bisimide ( AZP ) with an octyl chain and a zwitterionic group on the opposite imide positions of perylene tetracarboxylic dianhydride. The controllable nanostructures of AZP with tunable hydrophilic/hydrophobic surface have been investigated through solvent‐dependent amphiphilic self‐assembly as confirmed by SEM, TEM, and contact angle measurements. The planar perylene core of AZP contributes to strong π–π stacking, while the amphiphilic balance of asymmetric AZP adjusts the self‐assembly property. Additionally, due to intermolecular π–π stacking and solvent–solute interactions, AZP could self‐assemble into hydrophilic microtubes in a polar solvent (acetone) and hydrophobic nanofibers in an apolar solvent (hexane). This facile method provides a new pathway for controlling the surface properties based on an asymmetric amphiphilic zwitterionic perylene bisimide. 相似文献