Thiazole-fused androstenone and ethisterone derivatives: potent β- and γ-actin cytoskeleton inhibitors to treat melanoma tumors.

Autor:	Adhikary S; Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA malam@astate.edu., Roy S; Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA malam@astate.edu.; Enviromental Sciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA., Budhathoki S; Molecular Biosciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA., Chowdhury S; Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA malam@astate.edu.; Computer Science, The College of Engineering and Computer Science, Arkansas State University Jonesboro AR 72468 USA., Stillwell A; Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA malam@astate.edu., Basnakian AG; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences 4301 W. Markham St Little Rock AR 72205 USA.; Central Arkansas Veterans Healthcare System W. 7th St Little Rock AR 72205 USA., Tackett A; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock AR 72205 USA., Avaritt N; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences Little Rock AR 72205 USA., Milad M; The Department of Mathematics and Statistics, Arkansas State University Jonesboro AR 72467 USA., Alam MA; Department of Chemistry and Physics, College of Sciences and Mathematics, Arkansas State University Jonesboro Arkansas 72467 USA malam@astate.edu.; Enviromental Sciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA.; Molecular Biosciences Program, College of Sciences and Mathematics, Arkansas State University Jonesboro AR 72467 USA.; Arkansas Biosciences Institute, Arkansas State University Jonesboro AR 72467 USA.
Jazyk:	angličtina
Zdroj:	RSC medicinal chemistry [RSC Med Chem] 2024 Dec 06. Date of Electronic Publication: 2024 Dec 06.
DOI:	10.1039/d4md00719k
Abstrakt:	Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo . These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin ( ACTB ) and γ-actin ( ACTG1 ) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies. Competing Interests: Sanjay Adhikary was a graduate student in the biology department at Arkansas State University, Jonesboro, Arkansas, 72467, United States. Part of this manuscript was prepared as Sanjay's thesis. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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