Small molecule inhibitors targeting the cancers

MedComm, Journal Year: 2022, Volume and Issue: 3(4)

Published: Oct. 13, 2022

Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.

Language: Английский

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ALKBH5/MAP3K8 axis regulates PD-L1+ macrophage infiltration and promotes hepatocellular carcinoma progression

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(13), P. 5001 - 5018

Published: Jan. 1, 2022

Hepatocellular carcinoma is one of the most common malignant tumors.M6A a novel epigenetic modification that have been emerged as vital regulators for progression HCC.However, regulatory role, clinical significance and details modification, such impact on local tumor environment, remain largely unclear.Our study showed ALKBH5 was highly expressed in HCC high expression predicted worse prognosis patients.Prediction function by tissue samples single cell sequencing Gene Set Variation Analysis.Primary CD3 + T lymphocytes bone marrow-derived macrophages were used to evaluate effect immune microenvironment.The results indicated promote proliferation, metastasis PD-L1+macrophage recruitment.Mechanistically regulates MAP3K8 m6A dependent manner which mediates proliferation cells.ALKBH5 also promotes activation JNK ERK pathways through upregulating MAP3K8, thus regulating IL-8 promoting macrophage recruitment.Taken together, these data show growth, recruitment ALKBH5/MAP3K8 axis it may serve potential diagnostic marker target treatment patients.

Language: Английский

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Cyclin-dependent protein kinases and cell cycle regulation in biology and disease

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 12, 2025

Abstract Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as kinases able drive division. In reality, human genome contains 20 different CDKs, which can be divided in at least three sub-family with functions, mechanisms regulation, expression patterns and subcellular localization. Most these play fundamental roles normal physiology eucaryotic cells; therefore, their deregulation is associated onset and/or progression multiple disease including but not limited neoplastic neurodegenerative conditions. Here, we describe functions categorized into main functional groups they classified, highlighting most relevant pathways that functions. We then discuss potential CDKs pathologies, a particular focus on cancer, have extensively studied explored therapeutic targets. Finally, how inhibitors become standard therapies selected cancers propose novel ways investigation export targeting from cancer other chronic diseases. hope effort made collecting all available information both prominent lesser-known CDK family members will help identify develop areas research improve lives patients affected by debilitating

Language: Английский

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EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 29, 2024

Abstract Background Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness deemed inadequate, and the range targets limited. The aim this study was to identify early growth response 1 (EGR1) as transcription factor target in HCC explore role assess potential gene therapy utilizing EGR1 for management HCC. Methods In study, both vitro vivo assays were employed examine impact on mouse model human organoid assay utilized Additionally, molecular mechanism underlying regulation expression suppression by investigated. Results results our investigation revealed notable decrease promoted multiplication cells xenografted tumors. On other hand, excessive hindered proliferation repressed development Furthermore, efficacy validated using models hepatoma models, thereby providing additional substantiation anti-cancer mechanistic analysis demonstrated that interacted with promoter region phosphofructokinase-1, liver type (PFKL), leading repression PFKL consequent inhibition PFKL-mediated aerobic glycolysis. Moreover, sensitivity tumors sorafenib found be increased EGR1. Conclusion Our findings suggest possesses tumor suppressor HCC, may offer benefits patients.

Language: Английский

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CDK7 kinase activity promotes RNA polymerase II promoter escape by facilitating initiation factor release

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(12), P. 2287 - 2303.e10

Published: May 30, 2024

Cyclin-dependent kinase 7 (CDK7), part of the general transcription factor TFIIH, promotes gene by phosphorylating C-terminal domain RNA polymerase II (RNA Pol II). Here, we combine rapid CDK7 inhibition with multi-omics analysis to unravel direct functions in human cells. causes retention at promoters, leading decreased initiation and immediate global downregulation transcript synthesis. Elongation, termination, recruitment co-transcriptional factors are not directly affected. Although II, factors, Mediator accumulate complexes can also proceed into bodies without promoter-proximal pausing while retaining Mediator. Further downstream, phosphorylation increases released, allowing elongation an increase velocity. Collectively, activity release from facilitating escape promoter.

Language: Английский

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Chromatin damage generated by DNA intercalators leads to degradation of RNA Polymerase II

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(8), P. 4151 - 4166

Published: Feb. 10, 2024

Abstract In cancer therapy, DNA intercalators are mainly known for their capacity to kill cells by inducing damage. Recently, several have attracted much interest given ability inhibit RNA Polymerase I transcription (BMH-21), evict histones (Aclarubicin) or induce chromatin trapping of FACT (Curaxin CBL0137). Interestingly, these lack the damage while still retaining cytotoxic effects and stabilize p53. Herein, we report that impact biology interfering with stability polymerases I, II III. These three compounds degradation polymerase they simultaneously enable Topoisomerases TOP2A TOP2B on chromatin. addition, BMH-21 also acts as a catalytic inhibitor Topoisomerase II, resembling Aclarubicin. Moreover, induces histone chaperone propels accumulation Z-DNA eviction, similarly Aclarubicin CBL0137. cumulative general machinery topological defects impacting nuclear Therefore, capabilities may be result compounding deleterious homeostasis.

Language: Английский

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Structural basis of Cdk7 activation by dual T-loop phosphorylation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 3, 2024

Abstract Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating (CAK) part of transcription factor TFIIH. Cdk7 forms active complexes by associating with Cyclin H Mat1, regulated two phosphorylations the activation segment (T loop): canonical activating modification at T170 another S164. Here we report crystal structure human Cdk7/Cyclin H/Mat1 complex containing T-loop phosphorylations. Whereas pT170 coordinates basic residues conserved other CDKs, pS164 nucleates an arginine network unique ternary complex, involving all three subunits. We identify differential dependencies activity substrate recognition on individual CAK unaffected phosphorylation, whereas towards non-CDK substrates increased several-fold phosphorylation. Moreover, dual phosphorylation stimulates multisite RNA polymerase II (RNAPII) carboxy-terminal domain (CTD) SPT5 repeat (CTR) region. In cells, two-step process wherein S164 precedes, may prime, Thus, can regulate through multiple mechanisms, supporting tripartite formation possibly influencing processivity, while enhances key substrates.

Language: Английский

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Protein kinase CK2 – diverse roles in cancer cell biology and therapeutic promise

Molecular and Cellular Biochemistry, Journal Year: 2022, Volume and Issue: 478(4), P. 899 - 926

Published: Sept. 17, 2022

Language: Английский

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Emerging Implications of Phase Separation in Cancer

Advanced Science, Journal Year: 2022, Volume and Issue: 9(31)

Published: Sept. 18, 2022

Abstract In eukaryotic cells, biological activities are executed in distinct cellular compartments or organelles. Canonical organelles with membrane‐bound structures well understood. Cells also inherently contain versatile membrane‐less (MLOs) that feature liquid gel‐like bodies. A biophysical process termed liquid–liquid phase separation (LLPS) elucidates how MLOs form through dynamic biomolecule assembly. LLPS‐related molecules often have multivalency, which is essential for low‐affinity inter‐ intra‐molecule interactions to trigger separation. Accumulating evidence shows LLPS concentrates and organizes desired segregates unneeded cells. Thus, tunable functional specificity response environmental stimuli metabolic processes. Aberrant widely associated several hallmarks of cancer, including sustained proliferative signaling, growth suppressor evasion, cell death resistance, telomere maintenance, DNA damage repair, etc. Insights into the molecular mechanisms provide new insights cancer therapeutics. Here, current understanding emerging concepts its involvement comprehensively reviewed.

Language: Английский

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Nanomedicine as potential cancer therapy via targeting dysregulated transcription factors

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 89, P. 38 - 60

Published: Jan. 18, 2023

Language: Английский

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