Integrated Machine Learning and Chemoinformatics-Based Screening of Mycotic Compounds against Kinesin Spindle ProteinEg5 for Lung Cancer Therapy DOI Creative Commons
Priyanka Maiti, Priyanka Sharma, Mahesha Nand

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(5), P. 1639 - 1639

Published: March 2, 2022

Among the various types of cancer, lung cancer is second most-diagnosed worldwide. The kinesin spindle protein, Eg5, a vital protein behind bipolar mitotic establishment and maintenance during mitosis. Eg5 has been reported to contribute cell migration angiogenesis impairment no role in resting, non-dividing cells. Thus, it could be considered as target against several cancers, such renal urothelial carcinoma, prostate squamous etc. In recent years, fungal secondary metabolites from Indian Himalayan Region (IHR) have identified an important lead source drug development pipeline. Therefore, present study aims identify potential mycotic by applying integrated machine learning, chemoinformatics based silico-screening methods molecular dynamic simulation targeting cancer. Initially, library 1830 was screened predictive machine-learning model developed on random forest algorithm with high sensitivity (1) ROC area 0.99. Further, 319 out compounds active were evaluated for their drug-likeness properties four filters simultaneously, viz., Lipinski’s rule, CMC-50 like Veber Ghose filter. A total 13 passed all above docking, functional group analysis, line cytotoxicity prediction. Finally, hit found fungi IHR (−)-Cochlactone-A, Phelligridin C, Sterenin E, Cyathusal A. All efficient binding containing groups aromatic rings, carboxylic acid esters, carbonyl lines, namely, MCF-7, NCI-H226, NCI-H522, A549, NCI H187. dynamics confirms docked complex rigidity stability exploring root mean square deviations, fluctuations, radius gyration analysis 100 ns trajectories. used further develop effective drugs other

Language: Английский

Recent Advances in the Development of Pyrazole Derivatives as Anticancer Agents DOI Open Access
Yingqian Zhang,

Chenyuan Wu,

Nana Zhang

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(16), P. 12724 - 12724

Published: Aug. 12, 2023

Pyrazole derivatives, as a class of heterocyclic compounds, possess unique chemical structures that confer them with broad spectrum pharmacological activities. They have been extensively explored for designing potent and selective anticancer agents. In recent years, numerous pyrazole derivatives synthesized evaluated their potential against various cancer cell lines. Structure–activity relationship studies shown appropriate substitution on different positions the ring can significantly enhance efficacy tumor selectivity. It is noteworthy many demonstrated multiple mechanisms action by interacting targets including tubulin, EGFR, CDK, BTK, DNA. Therefore, this review summarizes current understanding structural features structure-activity relationships targets, aiming to facilitate development pyrazole-based drugs. We focus latest research advances in activities compounds reported from 2018 present.

Language: Английский

Citations

50
The two sides of chromosomal instability: drivers and brakes in cancer DOI Creative Commons
Rendy Hosea,

Sharon Hillary,

S. Hassan R. Naqvi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 29, 2024

Abstract Chromosomal instability (CIN) is a hallmark of cancer and associated with tumor cell malignancy. CIN triggers chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes chromosomes. arises errors DNA replication segregation during division, formation abnormal and/or structure Errors result licensing as well stress, such double-strand breaks stalled forks; meanwhile, stem defects machinery, centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, defective sister chromatids cohesion. In cells, deleterious damage, proteotoxic metabolic alteration, cycle arrest, senescence. Paradoxically, despite these negative consequences, one hallmarks found over 90% solid tumors blood cancers. Furthermore, could endow enhanced adaptation capabilities due increased intratumor heterogeneity, thereby facilitating adaptive resistance therapies; however, excessive induce death, “just-right” model for tumors. Elucidating complex nature crucial understanding dynamics tumorigenesis developing effective anti-tumor treatments. This review provides an overview causes consequences CIN, paradox phenomenon that continues perplex researchers. Finally, this explores potential CIN-based therapy.

Language: Английский

Citations

43
QSAR-based virtual screening of traditional Chinese medicine for the identification of mitotic kinesin Eg5 inhibitors DOI
Damilola S. Bodun, Damilola A. Omoboyowa, Olaposi Idowu Omotuyi

et al.

Computational Biology and Chemistry, Journal Year: 2023, Volume and Issue: 104, P. 107865 - 107865

Published: April 4, 2023

Language: Английский

Citations

26
Positioning centrioles and centrosomes DOI Creative Commons
Matthew R. Hannaford, Nasser M. Rusan

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 223(4)

Published: March 21, 2024

Centrosomes are the primary microtubule organizer in eukaryotic cells. In addition to shaping intracellular network and mitotic spindle, centrosomes responsible for positioning cilia flagella. To fulfill these diverse functions, must be properly located within cells, which requires that they undergo transport. Importantly, centrosome mispositioning has been linked ciliopathies, cancer, infertility. The mechanisms by migrate context dependent. many move via indirect motor transport, whereby centrosomal microtubules engage anchored proteins exert forces on those microtubules, resulting movement. However, some cases, direct or centriole functions as cargo directly binds molecular motors then walk stationary microtubules. this review, we summarize of motility consequences identify key questions remain addressed.

Language: Английский

Citations

14
The gene expression of CALD1, CDH2, and POSTN in fibroblast are related to idiopathic pulmonary fibrosis DOI Creative Commons
Shufei Wu,

Mengying Liu,

Mingrui Zhang

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 2, 2024

Introduction Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear. Methods RNA sequencing identified 475 differentially expressed genes (DEGs) in TGF-β1-induced primary model. Gene expression chips GSE101286 GSE110147 from NCBI gene omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs IPF samples. The ontology (GO) pathway enrichment, Protein-protein interaction (PPI) network construction, Maximal Clique Centrality (MCC) scoring performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), Western Blot, with siRNA used for knockdown. A co-expression was constructed GeneMANIA. Results GO enrichment highlighted significant of TGF-β cellular response, connective development, extracellular matrix components, signaling pathways such as AGE-RAGE ECM-receptor interaction. PPI analysis hub genes, including FN1, COL1A1, POSTN, KIF11, ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), POSTN (Periostin) dysregulated both GEO datasets. Validation experiments confirmed upregulation CALD1, CDH2, TGF-β1-treated fibroblasts IHC probed tissue-level patterns these three molecules. Knockdown attenuated fibrotic markers (collagen I α-SMA) response TGF-β1 stimulation fibroblasts. Co-expression revealed interactions between predicted involved actin cytoskeleton regulation cell-cell junction organization. Conclusions potential contributors fibrosis, present promising therapeutic targets patients.

Language: Английский

Citations

11
In-silico-based lead optimization of hit compounds targeting mitotic kinesin Eg5 for cancer management DOI
Damilola S. Bodun, Damilola A. Omoboyowa,

Victor F. Olofinlade

et al.

In Silico Pharmacology, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 7, 2025

Language: Английский

Citations

1
Kinesin Spindle Protein Inhibitors in Cancer: From High Throughput Screening to Novel Therapeutic Strategies DOI Creative Commons
Rand Shahin, Salah Aljamal

Future Science OA, Journal Year: 2022, Volume and Issue: 8(3)

Published: Feb. 21, 2022

Bringing to a halt the cell cycle in mitosis and interfering with its normal progression is one of most successful anti-cancer strategies used nowadays. Classically, several kinds drugs like taxanes vinca alkaloids directly inhibit microtubules during division. These exhibit serious side effects, importantly, severe peripheral neuropathies. Alternatively, KSP inhibitors are grasping lot research attention as less toxic mitotic inhibitors. In this review, we track medicinal chemistry developmental stages Moreover, address challenges that faced development inhibitor therapy for cancer future insights latest advances directed find active drugs.

Language: Английский

Citations

36
Polyploidy in Cancer: Causal Mechanisms, Cancer-Specific Consequences, and Emerging Treatments DOI Open Access
Patrick Conway,

Jonathan Dao,

Dmytro Kovalskyy

et al.

Molecular Cancer Therapeutics, Journal Year: 2024, Volume and Issue: 23(5), P. 638 - 647

Published: Feb. 5, 2024

Abstract Drug resistance is the major determinant for metastatic disease and fatalities, across all cancers. Depending on tissue of origin therapeutic course, a variety biological mechanisms can support sustain drug resistance. Although genetic mutations gene silencing through epigenetic are culprits in targeted therapy, efflux polyploidization more global that prevail broad range pathologies, response to treatments. There an unmet need identify patients at risk polyploidy, understand underlying polyploidization, develop strategies predict, limit, reverse polyploidy thus enhancing efficacy standard-of-care therapy improve better outcomes. This literature review provides overview cancer offers perspective patient monitoring actionable therapy.

Language: Английский

Citations

5
The role of kinesin family members in hepatobiliary carcinomas: from bench to bedside DOI Creative Commons
Kai Zhao, Xiangyu Li,

Yunxiang Feng

et al.

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: March 3, 2024

As a major component of the digestive system malignancies, tumors originating from hepatic and biliary ducts seriously endanger public health. The kinesins (KIFs) are molecular motors that enable microtubule-dependent intracellular trafficking necessary for mitosis meiosis. Normally, stability KIFs is essential to maintain cell proliferation genetic homeostasis. However, aberrant activity may destroy this dynamic stability, leading uncontrolled division tumor initiation. In work, we have made an integral summarization specific roles in hepatocellular duct carcinogenesis, referring signal transduction potential prognostic evaluation. Additionally, current clinical applications KIFs-targeted inhibitors also been discussed, including their efficacy advantages, relationship with drug sensitivity or resistance, feasibility combination chemotherapy other targeted agents, as well corresponding trials. conclusion, abnormally activated participate regulation progression via diverse range mechanisms closely associated prognosis. Meanwhile, KIFs-aimed carry out promising tumor-targeted therapeutic strategy deserves be further investigated hepatobiliary carcinoma (HBC).

Language: Английский

Citations

5
Mechanisms of minor pole–mediated spindle bipolarization in human oocytes DOI
Tianyu Wu, Yuxi Luo, Meiling Zhang

et al.

Science, Journal Year: 2024, Volume and Issue: 385(6711)

Published: Aug. 22, 2024

Spindle bipolarization, the process of a microtubule mass transforming into bipolar spindle, is prerequisite for accurate chromosome segregation. In contrast to mitotic cells, and mechanism spindle bipolarization in human oocytes remains unclear. Using high-resolution imaging more than 1800 oocytes, we revealed typical state multipolar intermediates that form during elucidated underlying this process. We found minor poles formed multiple kinetochore clusters contribute generation intermediates. further determined essential roles HAUS6, KIF11, KIF18A identified mutations these genes infertile patients characterized by oocyte or embryo defects. These results provide insights physiological pathological mechanisms oocytes.

Language: Английский

Citations

5