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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Rational Design, Synthesis, and Biological Evaluation of Novel c-Met Degraders for Lung Cancer Therapy

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to inhibitors, emerged hamper their application in clinical treatment. Degradation of offers opportunity solve these issues. In this study, we developed a series degraders, and optimal compound 22b can efficiently degrade with DC50 value 0.59 nM EBC-1 cells. Mechanistic studies revealed that induced degradation via proteasome-mediated pathway. addition, suppressed proliferation also apoptosis cells, outperforming corresponding inhibitor tepotinib. Importantly, showed favorable pharmacokinetic properties significantly tumor regression xenograft model without obvious toxicity. brief, study provided as novel degrader lung cancer therapy.

Language: Английский

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Thirty years of NRF2: advances and therapeutic challenges

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Language: Английский

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Discovery and significance of protein-protein interactions in health and disease

Cell, Journal Year: 2024, Volume and Issue: 187(23), P. 6501 - 6517

Published: Nov. 1, 2024

The identification of individual protein-protein interactions (PPIs) began more than 40 years ago, using protein affinity chromatography and antibody co-immunoprecipitation. As new technologies emerged, analysis PPIs increased to a genome-wide scale with the introduction intracellular tagging methods, purification (AP) followed by mass spectrometry (MS), co-fractionation MS (CF-MS). Now, combining resulting catalogs complementary including crosslinking (XL-MS) cryogenic electron microscopy (cryo-EM), helps distinguish direct from indirect ones within same or between different complexes. These powerful approaches promise artificial intelligence applications like AlphaFold herald future where complexes, energy-driven machines, will be understood in exquisite detail, unlocking insights contexts both basic biology disease.

Language: Английский

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Mechanisms and regulation of substrate degradation by the 26S proteasome

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Language: Английский

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Zinc finger proteins: guardians of genome stability

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 25, 2024

Zinc finger proteins (ZNF), a unique yet diverse group of proteins, play pivotal roles in fundamental cellular mechanisms including transcription regulation, chromatin remodeling, protein/RNA homeostasis, and DNA repair. Consequently, the mis regulation ZNF can result variety human diseases, ranging from neurodevelopmental disorders to several cancers. Considering promising results damage repair (DDR) inhibition clinic, as therapeutic strategy for patients with homologous recombination (HR) deficiency, identifying other potential targetable DDR emerged vulnerabilities resistant tumor cells is essential, especially when considering burden acquired drug resistance. Importantly, there are growing number studies new ZNFs revealing their significance pathways, highlighting great targets DDR-inhibition therapy. Although, still many uncharacterized ZNF-containing unknown biological function. In this review, we highlight major classes observed functions mammalian cells. We briefly introduce well-known newly discovered describe molecular contributions health disease, cancer. Finally, discuss mechanisms, cancer therapy advances exploiting future disease.

Language: Английский

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The value of protein allostery in rational anticancer drug design: an update

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(9), P. 1071 - 1085

Published: July 28, 2024

Introduction Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from into which ligand dock and do not account for exactly how site is altered. Favorable inhibitors nearby follow nature, mimicking diverse regulation strategies.

Language: Английский

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CUL4-Based Ubiquitin Ligases in Chromatin Regulation: An Evolutionary Perspective

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 63 - 63

Published: Jan. 7, 2025

Ubiquitylation is a post-translational modification that modulates protein function and stability. It orchestrated by the concerted action of three types enzymes, with substrate specificity governed ubiquitin ligases (E3s), which may exist as single proteins or part multi-protein complexes. Although Cullin (CUL) lack intrinsic enzymatic activity, they participate in formation active ligase complexes, known Cullin-Ring Ligases (CRLs), through their association ROC1 ROC2, along adaptor receptor proteins. Mammalian genomes encode several CUL (CUL1-9), each contributing to distinct CRLs. Among these proteins, CUL1, CUL3, CUL4 are believed be most ancient evolutionarily conserved from yeast mammals, uniquely duplicated vertebrates. Genetic evidence strongly implicates CUL4-based (CRL4s) chromatin regulation across various species suggests that, vertebrates, CRL4s have also acquired cytosolic role, facilitated cytosol-localizing paralog CUL4. Substrates identified biochemical studies elucidated molecular mechanisms regulate processes. The substantial body knowledge on biology amassed over past two decades provides unique opportunity explore functional evolution CRL4. In this review, we synthesize available structural, genetic, data CRL4 model organisms discuss novel functions CRL4s.

Language: Английский

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Emerging Trends in DNA Nanotechnology-Enabled Cell Surface Engineering

JACS Au, Journal Year: 2025, Volume and Issue: 5(2), P. 550 - 570

Published: Feb. 6, 2025

Cell surface engineering is a rapidly advancing field, pivotal for understanding cellular physiology and driving innovations in biomedical applications. In this regard, DNA nanotechnology offers unprecedented potential precisely manipulating functionalizing cell surfaces by virtue of its inherent programmability versatile functionalities. Herein, Perspective provides comprehensive overview emerging trends engineering, focusing on key nanostructure-based tools, their roles regulating physiological processes, We first discuss the strategies integrating molecules onto surfaces, including attachment oligonucleotides higher-order nanostructure. Second, we summarize impact DNA-based various such as membrane protein degradation, signaling transduction, intercellular communication, construction artificial components. Third, highlight applications DNA-engineered targeted therapies cancer inflammation, well capture/protection diagnostic detection. Finally, address challenges future directions nanotechnology-based engineering. This aims to provide valuable insights rational design contributing development precise personalized medicine.

Language: Английский

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Reprograming of the ubiquitin ligase Ubr1 by intrinsically disordered Roq1 through cooperating multifunctional motifs

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

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