CDK2
目录号 : GC35631
CDK2 是真核S/T蛋白激酶家族的成员,功能是催化 ATPγ 磷酸转移,活性 CDK2 与短肽 (HHASPRK) 底物形成复合物。
Cas No.:255064-79-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
CDK2 is a member of the eukaryotic S/T protein kinase family and its function is to catalyze the phosphoryl transfer of ATP γ-phosphate to serine or threonine hydroxyl (denoted as S0/T0) in a protein substrate.
CDK2 (Cyclin-dependent kinase 2) is a member of the eukaryotic S/T protein kinase family and its function is to catalyze the phosphoryl transfer of ATP γ-phosphate to serine or threonine hydroxyl (denoted as S0/T0) in a protein substrate. The fully active CDK2 is in complex with HHASPRK (an optimal peptide substrate), namely interactions of CDK2 with peptide substrate and the dynamics of the G-loop. CDK2 participates in eukaryotic cell cycle regulation at the G1/S boundary. CDK2 deregulation has been proved to occur in tumor cells, evoking a strong interest in artificial and native inhibitors. CDK2 activity is tightly regulated by a complex mechanism, including a positive regulatory subunit binding, and phosphorylations at positive and/or negative regulatory sites[1].
[1]. BÁrtovÁ I, The mechanism of inhibition of the cyclin-dependent kinase-2 as revealed by the molecular dynamics study on the complex CDK2 with the peptide substrate HHASPRK. Protein Sci. 2005 Feb;14(2):445-51.
| Cas No. | 255064-79-0 | SDF | |
| 分子式 | C35H57N15O9 | 分子量 | 831.92 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.202 mL | 6.0102 mL | 12.0204 mL |
| 5 mM | 0.2404 mL | 1.202 mL | 2.4041 mL |
| 10 mM | 0.1202 mL | 0.601 mL | 1.202 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Targeting CDK2 in cancer: challenges and opportunities for therapy
Drug Discov Today 2020 Feb;25(2):406-413.PMID:31839441DOI:10.1016/j.drudis.2019.12.001.
Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2 and its regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.
Cyclin E/CDK2: DNA Replication, Replication Stress and Genomic Instability
Front Cell Dev Biol 2021 Nov 24;9:774845.PMID:34901021DOI:10.3389/fcell.2021.774845.
DNA replication must be precisely controlled in order to maintain genome stability. Transition through cell cycle phases is regulated by a family of Cyclin-Dependent Kinases (CDKs) in association with respective cyclin regulatory subunits. In normal cell cycles, E-type cyclins (Cyclin E1 and Cyclin E2, CCNE1 and CCNE2 genes) associate with CDK2 to promote G1/S transition. Cyclin E/CDK2 complex mostly controls cell cycle progression and DNA replication through phosphorylation of specific substrates. Oncogenic activation of Cyclin E/CDK2 complex impairs normal DNA replication, causing replication stress and DNA damage. As a consequence, Cyclin E/CDK2-induced replication stress leads to genomic instability and contributes to human carcinogenesis. In this review, we focus on the main functions of Cyclin E/CDK2 complex in normal DNA replication and the molecular mechanisms by which oncogenic activation of Cyclin E/CDK2 causes replication stress and genomic instability in human cancer.
AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss
Eur J Med Chem 2021 Dec 15;226:113849.PMID:34560429DOI:10.1016/j.ejmech.2021.113849.
Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of hearing loss and cancer. Previously, we identified AZD5438 and AT7519-7 as potent inhibitors of CDK2, however, they also targeted additional kinases, leading to unwanted toxicities. Proteolysis Targeting Chimeras (PROTACs) are a new promising class of small molecules that can effectively direct specific proteins to proteasomal degradation. Herein we report the design, synthesis, and characterization of PROTACs of AT7519-7 and AZD5438 and the identification of PROTAC-8, an AZD5438-PROTAC, that exhibits selective, partial CDK2 degradation. Furthermore, PROTAC-8 protects against cisplatin ototoxicity and kainic acid excitotoxicity in zebrafish. Molecular dynamics simulations reveal the structural requirements for CDK2 degradation. Together, PROTAC-8 is among the first-in-class PROTACs with in vivo therapeutic activities and represents a new lead compound that can be further developed for better efficacy and selectivity for CDK2 degradation against hearing loss and cancer.
Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis
Front Cell Dev Biol 2021 Jul 30;9:682002.PMID:34409029DOI:10.3389/fcell.2021.682002.
Background: Tumor microenvironment (TME) plays important roles in different cancers. Our study aimed to identify molecules with significant prognostic values and construct a relevant Nomogram, immune model, competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD). Methods: "GEO2R," "limma" R packages were used to identify all differentially expressed mRNAs from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Genes with P-value <0.01, LogFC>2 or <-2 were included for further analyses. The function analysis of 250 overlapping mRNAs was shown by DAVID and Metascape software. By UALCAN, Oncomine and R packages, we explored the expression levels, survival analyses of CDK2 in 33 cancers. "Survival," "survminer," "rms" R packages were used to construct a Nomogram model of age, gender, stage, T, M, N. Univariate and multivariate Cox regression were used to establish prognosis-related immune forecast model in LUAD. CeRNA network was constructed by various online databases. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore correlations between CDK2 expression and IC50 of anti-tumor drugs. Results: A total of 250 differentially expressed genes (DEGs) were identified to participate in many cancer-related pathways, such as activation of immune response, cell adhesion, migration, P13K-AKT signaling pathway. The target molecule CDK2 had prognostic value for the survival of patients in LUAD (P = 5.8e-15). Through Oncomine, TIMER, UALCAN, PrognoScan databases, the expression level of CDK2 in LUAD was higher than normal tissues. Pan-cancer analysis revealed that the expression, stage and survival of CDK2 in 33 cancers, which were statistically significant. Through TISIDB database, we selected 13 immunodepressants, 21 immunostimulants associated with CDK2 and explored 48 genes related to these 34 immunomodulators in cBioProtal database (P < 0.05). Gene Set Enrichment Analysis (GSEA) and Metascape indicated that 49 mRNAs were involved in PUJANA ATM PCC NETWORK (ES = 0.557, P = 0, FDR = 0), SIGNAL TRANSDUCTION (ES = -0.459, P = 0, FDR = 0), immune system process, cell proliferation. Forest map and Nomogram model showed the prognosis of patients with LUAD (Log-Rank = 1.399e-08, Concordance Index = 0.7). Cox regression showed that four mRNAs (SIT1, SNAI3, ASB2, and CDK2) were used to construct the forecast model to predict the prognosis of patients (P < 0.05). LUAD patients were divided into two different risk groups (low and high) had a statistical significance (P = 6.223e-04). By "survival ROC" R package, the total risk score of this prognostic model was AUC = 0.729 (SIT1 = 0.484, SNAI3 = 0.485, ASB2 = 0.267, CDK2 = 0.579). CytoHubba selected ceRNA mechanism medicated by potential biomarkers, 6 lncRNAs-7miRNAs-CDK2. The expression of CDK2 was associated with IC50 of 89 antitumor drugs, and we showed the top 20 drugs with P < 0.05. Conclusion: In conclusion, our study identified CDK2 related immune forecast model, Nomogram model, forest map, ceRNA network, IC50 of anti-tumor drugs, to predict the prognosis and guide targeted therapy for LUAD patients.
Inhibition of the CDK2 and Cyclin A complex leads to autophagic degradation of CDK2 in cancer cells
Nat Commun 2022 May 20;13(1):2835.PMID:35595767DOI:10.1038/s41467-022-30264-0.
Cyclin-dependent kinase 2 (CDK2) complex is significantly over-activated in many cancers. While it makes CDK2 an attractive target for cancer therapy, most inhibitors against CDK2 are ATP competitors that are either nonspecific or highly toxic, and typically fail clinical trials. One alternative approach is to develop non-ATP competitive inhibitors; they disrupt interactions between CDK2 and either its partners or substrates, resulting in specific inhibition of CDK2 activities. In this report, we identify two potential druggable pockets located in the protein-protein interaction interface (PPI) between CDK2 and Cyclin A. To target the potential druggable pockets, we perform a LIVS in silico screening of a library containing 1925 FDA approved drugs. Using this approach, homoharringtonine (HHT) shows high affinity to the PPI and strongly disrupts the interaction between CDK2 and cyclins. Further, we demonstrate that HHT induces autophagic degradation of the CDK2 protein via tripartite motif 21 (Trim21) in cancer cells, which is confirmed in a leukemia mouse model and in human primary leukemia cells. These results thus identify an autophagic degradation mechanism of CDK2 protein and provide a potential avenue towards treating CDK2-dependent cancers.