288 results match your criteria cdks selective

Exploring multi-target inhibitors using approach targeting cell cycle dysregulator-CDK proteins.

J Biomol Struct Dyn 2021 Apr 30:1-15. Epub 2021 Apr 30.

Department of Bioinformatics, Hazara University, Mansehra, Pakistan.

Cyclin-dependent kinases (CDKs) belong to a family of multifunctional enzymes that control cell cycle modifications, transcription, and cell proliferation. Their dysfunctions result in different diseases like cancer making them an important drug target in oncology and beyond. The present study aims at identifying the selective inhibitors for ATP binding site in CDK proteins (CDK1, CDK2, CDK4, and CDK5) following a multi-target drug designing approach. Read More

View Article and Full-Text PDF

Ampelopsin Inhibits Cell Proliferation and Induces Apoptosis in HL60 and K562 Leukemia Cells by Downregulating AKT and NF-κB Signaling Pathways.

Int J Mol Sci 2021 Apr 20;22(8). Epub 2021 Apr 20.

Department of Life Science and Biochemical Engineering, Sun Moon University, Asan 31460, Korea.

Leukemia is a type of blood cancer caused by the rapid proliferation of abnormal white blood cells. Currently, several treatment options, including chemotherapy, radiation therapy, and bone marrow transplantation, are used to treat leukemia, but the morbidity and mortality rates of patients with leukemia are still high. Therefore, there is still a need to develop more selective and less toxic drugs for the effective treatment of leukemia. Read More

View Article and Full-Text PDF

Predictive hybrid paradigm for cytotoxic activity of 1,3,4-thiadiazole derivatives as CDK6 inhibitors against human (MCF-7) breast cancer cell line and its structural modifications: rational for novel cancer therapeutics.

J Biomol Struct Dyn 2021 Apr 23:1-20. Epub 2021 Apr 23.

Department of Microbiology, School of Sciences (SOS), Federal University of Technology Akure, Akure, Nigeria.

The dysregulation of cyclin-CDK6 interactions has been implicated in human breast cancer, providing a rationale for more therapeutic options. Recently, ATP-competitive inhibitors have been employed for managing breast cancer. These molecules, like most natural CDKs inhibitors, potently bind in the ATP-binding site of CDK6 to regulate trans-activation. Read More

View Article and Full-Text PDF

Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action.

Int J Mol Sci 2021 Mar 10;22(6). Epub 2021 Mar 10.

Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstancow Wlkp. 72 Av., 70-111 Szczecin, Poland.

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. Read More

View Article and Full-Text PDF

Discovery and resistance mechanism of a selective CDK12 degrader.

Nat Chem Biol 2021 Mar 22. Epub 2021 Mar 22.

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.

Cyclin-dependent kinase 12 (CDK12) is an emerging therapeutic target due to its role in regulating transcription of DNA-damage response (DDR) genes. However, development of selective small molecules targeting CDK12 has been challenging due to the high degree of homology between kinase domains of CDK12 and other transcriptional CDKs, most notably CDK13. In the present study, we report the rational design and characterization of a CDK12-specific degrader, BSJ-4-116. Read More

View Article and Full-Text PDF

A novel histone deacetylase inhibitor MPT0L184 dysregulates cell-cycle checkpoints and initiates unscheduled mitotic signaling.

Biomed Pharmacother 2021 Jun 16;138:111485. Epub 2021 Mar 16.

Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan. Electronic address:

Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. Read More

View Article and Full-Text PDF

Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models.

Cell Death Discov 2021 Mar 15;7(1):54. Epub 2021 Mar 15.

Department of Medicine Clinic III - Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock University Medical Centre, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany.

Current therapeutic approaches have met limited clinical success for glioblastoma multiforme (GBM). Since GBM harbors genomic alterations in cyclin-dependent kinases (CDKs), targeting these structures with specific inhibitors (CDKis) is promising. Here, we describe the antitumoral potential of selective CDKi on low-passage GBM 2D- and 3D models, cultured as neurospheres (NSCs) or glioma stem-like cells (GSCs). Read More

View Article and Full-Text PDF

Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents.

Eur J Med Chem 2021 Mar 2;214:113244. Epub 2021 Feb 2.

School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia. Electronic address:

Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Read More

View Article and Full-Text PDF

Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs.

Acta Pharm Sin B 2021 Jan 23;11(1):30-54. Epub 2020 May 23.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer. The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs. In particular, third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition, exhibiting a perfect balance between anticancer efficacy and general toxicity. Read More

View Article and Full-Text PDF
January 2021

Targeted brachyury degradation disrupts a highly specific autoregulatory program controlling chordoma cell identity.

Cell Rep Med 2021 Jan 19;2(1):100188. Epub 2021 Jan 19.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Chordomas are rare spinal tumors addicted to expression of the developmental transcription factor brachyury. In chordomas, brachyury is super-enhancer associated and preferentially downregulated by pharmacologic transcriptional CDK inhibition, leading to cell death. To understand the underlying basis of this sensitivity, we dissect the brachyury transcription regulatory network and compare the consequences of brachyury degradation with transcriptional CDK inhibition. Read More

View Article and Full-Text PDF
January 2021

Discovery of selective CDK9 degraders with enhancing antiproliferative activity through PROTAC conversion.

Eur J Med Chem 2021 Feb 10;211:113091. Epub 2020 Dec 10.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

Cyclin-dependent kinase 9 (CDK9) is an increasingly important potential cancer treatment target. Nowadays, developing selective CDK9 inhibitors has been extremely challenging as its ATP-binding sites are similar with other CDKs. Here, we report that the CDK9 inhibitor BAY-1143572 is converted into a series of proteolysis targeting chimeras (PROTACs) which leads to several compounds inducing the degradation of CDK9 in acute myeloid leukemia cells at a low nanomolar concentration. Read More

View Article and Full-Text PDF
February 2021

Systematic mapping of cancer cell target dependencies using high-throughput drug screening in triple-negative breast cancer.

Comput Struct Biotechnol J 2020 24;18:3819-3832. Epub 2020 Nov 24.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

While high-throughput drug screening offers possibilities to profile phenotypic responses of hundreds of compounds, elucidation of the cell context-specific mechanisms of drug action requires additional analyses. To that end, we developed a computational target deconvolution pipeline that identifies the key target dependencies based on collective drug response patterns in each cell line separately. The pipeline combines quantitative drug-cell line responses with drug-target interaction networks among both intended on- and potent off-targets to identify pharmaceutically actionable and selective therapeutic targets. Read More

View Article and Full-Text PDF
November 2020

Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling.

Bioorg Chem 2020 10 26;103:104222. Epub 2020 Aug 26.

Drug Design and Discovery Lab, Zewail City of Science and Technology, Cairo 12578, Cairo, Egypt; University of Science and Technology, Zewail City of Science and Technology, Cairo 12578, Cairo, Egypt. Electronic address:

VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. Read More

View Article and Full-Text PDF
October 2020

CDK4 and CDK5 Inhibition Have Comparable Mild Hypothermia Effects in Preventing Drp1-Dependent Mitochondrial Fission and Neuron Death Induced by MPP.

Mol Neurobiol 2020 Oct 15;57(10):4090-4105. Epub 2020 Jul 15.

Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, 701, Taiwan, Republic of China.

Mild hypothermia has promising effects in the treatment of acute brain insults and also affects cell cycle progression. Mitochondrial dynamics, fusion and fission, are changed along with the cell cycle and disrupted in neurodegenerative diseases, including Parkinson's disease (PD). However, the effects of hypothermia on aberrant mitochondrial dynamics in PD remain unknown. Read More

View Article and Full-Text PDF
October 2020

Phenotypic Characterization of Targeted Knockdown of Cyclin-Dependent Kinases in the Intestinal Epithelial Cells.

Toxicol Sci 2020 09;177(1):226-234

Drug Safety Research and Development, Pfizer Inc., San Diego, California 92121.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases that regulate cell cycle and have been vigorously pursued as druggable targets for cancer. There are over 20 members of the CDK family. Given their structural similarity, selective inhibition by small molecules has been elusive. Read More

View Article and Full-Text PDF
September 2020

Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity.

Eur J Med Chem 2020 Aug 15;200:112424. Epub 2020 May 15.

School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China. Electronic address:

Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Read More

View Article and Full-Text PDF

CDK7 inhibitors as anticancer drugs.

Cancer Metastasis Rev 2020 09;39(3):805-823

Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.

Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Read More

View Article and Full-Text PDF
September 2020

Mcl-1 as a "barrier" in cancer treatment: Can we target it now?

Int Rev Cell Mol Biol 2020 5;351:23-55. Epub 2020 Feb 5.

Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, Russia. Electronic address:

During the last two decades, the study of Mcl-1, an anti-apoptotic member of the Bcl-2 family, attracted researchers due to its important role in cancer cell survival and tumor development. The significance of Mcl-1 protein in resistance to chemotherapeutics makes it an attractive target in cancer therapy. Here, we discuss the diverse possibilities for indirect Mcl-1 inhibition through its downregulation, for example, via targeting for proteasomal degradation or blockage of translation and transcription. Read More

View Article and Full-Text PDF
October 2020

Discovery of thiazole-based-chalcones and 4-hetarylthiazoles as potent anticancer agents: Synthesis, docking study and anticancer activity.

Bioorg Chem 2020 05 14;98:103761. Epub 2020 Mar 14.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.

The crucial need for novel antitumor agents with high selectivity toward cancer cells has promoted us to synthesize new series of thiazole-based chalcones and 4-hetarylthiazoles (rigid chalcones). The synthesis of thiazolyl chalcones and 4-hetarylthiazoles and the assertion of their structure are described. Their anti-proliferative activity was estimated against three human cancer cell lines; HepG-2, A549 and MCF-7. Read More

View Article and Full-Text PDF

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer.

Int J Mol Sci 2020 Mar 13;21(6). Epub 2020 Mar 13.

Lab of Biochemistry & Molecular Biology, School of Life Sciences, Yunnan University, Kunming 650091, China.

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. Read More

View Article and Full-Text PDF

Development of a CDK10/CycM Kinase Screening Assay and Identification of First Small-Molecule Inhibitors.

Front Chem 2020 27;8:147. Epub 2020 Feb 27.

Laboratory of Integrative Biology of Marine Models, Station Biologique de Roscoff, Sorbonne Université/CNRS, Roscoff, France.

Cyclin-dependent kinases (CDKs) constitute a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of numerous important molecular and cellular processes. CDKs have long been considered promising therapeutic targets in a variety of pathologies, and the recent therapeutic success of CDK4/6 inhibitors in breast cancers has renewed interest in their therapeutic potential. Small-molecule inhibitors have been identified for every human CDK, except for CDK10. Read More

View Article and Full-Text PDF
February 2020

A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib.

Pharmacol Res 2020 06 14;156:104686. Epub 2020 Feb 14.

Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore; Department of Pharmacology, National University of Singapore, Singapore; Department of Medicine, National University Cancer Institute Singapore, National University Health System, Singapore. Electronic address:

Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Read More

View Article and Full-Text PDF

CDK1 in Breast Cancer: Implications for Theranostic Potential.

Anticancer Agents Med Chem 2020 ;20(7):758-767

Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Breast cancer has been identified as one of the main cancer-related deaths among women during some last decades. Recent advances in the introduction of novel potent anti-cancer therapeutics in association with early detection methods led to a decrease in the mortality rate of breast cancer. However, the scenario of breast cancer is yet going on and further improvements in the current anti-cancer therapeutic approaches are needed. Read More

View Article and Full-Text PDF
January 2020

Discovery of a novel and highly selective CDK9 kinase inhibitor (JSH-009) with potent antitumor efficacy in preclinical acute myeloid leukemia models.

Invest New Drugs 2020 10 23;38(5):1272-1281. Epub 2019 Dec 23.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui, 230031, People's Republic of China.

Acute myeloid leukemia (AML) is reported to be vulnerable to transcription disruption due to transcriptional addiction. Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, has attracted extensive attention as a drug target. Although several inhibitors, such as alvocidib and dinaciclib, have shown potent therapeutic effects in clinical trials on AML, the lack of high selectivity for CDK9 and other CDKs has limited their optimal clinical efficacy. Read More

View Article and Full-Text PDF
October 2020

Development of selective mono or dual PROTAC degrader probe of CDK isoforms.

Eur J Med Chem 2020 Feb 6;187:111952. Epub 2019 Dec 6.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China; Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China. Electronic address:

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. Read More

View Article and Full-Text PDF
February 2020

Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective.

J Biomol Struct Dyn 2020 Oct 6;38(17):5126-5135. Epub 2019 Dec 6.

Structural Bioinformatics Lab, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, HP, India.

Cyclin-dependent kinases (CDKs) are known for their vital role in regulating cell cycle progression through protein-kinase interactions. CDKs also help in regulating transcription and development of the central nervous system. Inhibition of CDKs is a very fundamental approach for drug discovery in areas of different types of cancers, Alzheimer's, and HIV infections. Read More

View Article and Full-Text PDF
October 2020

Suppression of Angiogenesis by Targeting Cyclin-Dependent Kinase 7 in Human Umbilical Vein Endothelial Cells and Renal Cell Carcinoma: An In Vitro and In Vivo Study.

Cells 2019 11 19;8(11). Epub 2019 Nov 19.

Department of Urology, College of Medicine, National Taiwan University, and National Taiwan University Hospital, Taipei 100, Taiwan.

Cancer cells rely on aberrant transcription for growth and survival. Cyclin-dependent kinases (CDKs) play critical roles in regulating gene transcription by modulating the activity of RNA polymerase II (RNAPII). THZ1, a selective covalent inhibitor of CDK7, has antitumor effects in several human cancers. Read More

View Article and Full-Text PDF
November 2019

Therapeutic Targeting of CDK12/CDK13 in Triple-Negative Breast Cancer.

Cancer Cell 2019 11 24;36(5):545-558.e7. Epub 2019 Oct 24.

Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. Electronic address:

Epigenetic regulation enables tumors to respond to changing environments during tumor progression and metastases and facilitates treatment resistance. Targeting chromatin modifiers or catalytic effectors of transcription is an emerging anti-cancer strategy. The cyclin-dependent kinases (CDKs) 12 and 13 phosphorylate the C-terminal domain of RNA polymerase II, regulating transcription and co-transcriptional processes. Read More

View Article and Full-Text PDF
November 2019

Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach.

Expert Opin Investig Drugs 2019 Nov 22;28(11):989-1001. Epub 2019 Oct 22.

Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.

: Despite advancements over the last 2 years, outcomes for acute myeloid leukemia (AML) are poor; however, a greater comprehension of disease mechanisms has driven the investigation of new targeted treatments. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, transcription and DNA repair, and are aberrantly expressed in AML. Targeting the CDK pathway is an emerging promising therapeutic strategy in AML. Read More

View Article and Full-Text PDF
November 2019

Characterizing CDK8/19 Inhibitors through a NFκB-Dependent Cell-Based Assay.

Cells 2019 10 6;8(10). Epub 2019 Oct 6.

Department of Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA.

Cell-based assays for CDK8/19 inhibition are not easily defined, since there are no known cellular functions unique to these kinases. To solve this problem, we generated derivatives of 293 cells with CRISPR knockout of one or both of CDK8 and CDK19. Double knockout (dKO) of CDK8 and CDK19 together (but not individually) decreased the induction of transcription by NFκB (a CDK8/19-potentiated transcription factor) and abrogated the effect of CDK8/19 inhibitors on such induction. Read More

View Article and Full-Text PDF
October 2019