Designing Specific HSP70 Substrate Binding Domain Inhibitor for Perturbing Protein Folding Pathways to Inhibit Cancer Mechanism

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dc.authoridGumus, Mehmet/0000-0001-9262-7940
dc.authoridTUTAR, Yusuf/0000-0003-2613-9644
dc.authoridSERT, YUSUF/0000-0001-8836-8667
dc.authoridKOCA, IRFAN/0000-0001-7873-159X
dc.contributor.authorCoskun, Kubra A.
dc.contributor.authorKoca, Irfan
dc.contributor.authorGumus, Mehmet
dc.contributor.authorTutar, Yusuf
dc.date.accessioned2024-10-26T18:10:52Z
dc.date.available2024-10-26T18:10:52Z
dc.date.issued2021
dc.departmentSivas Cumhuriyet Üniversitesi
dc.description.abstractBackground: HSP70 is a survival factor for tumor cells in transformation and in tumor progression as well as in anti-apoptotic response. Objective: Several inhibitors targeting HSP70 ATPase function displayed off-target effects, but PES, which targets the HSP70 substrate binding domain, prevents tumor cell survival prominently. However, PES may not bind HSP70 in the absence of nucleotide. This research aimed to design a unique inhibitor molecule that works both in the presence and absence of nucleotides to amplify inhibition. Methods: A set of chimeric coumarine-pyrazole derivatives were determined by in silico techniques and synthesized to elucidate their inhibitory effects. Cell viability experiments displayed KBR1307 as the most efficient inhibitor. A set of characterization experiments were performed, and the results were compared to that of PES agent. Binding constant, ATP hydrolysis rate, and percent aggregation were determined in the presence and absence of inhibitors. Results: In silico docking experiments showed that only KBR1307 binds the HSP70 substrate binding domain and interacts with cochaperone interface. Binding experiments indicated that KBR1307 binds HSP70 both in the presence and absence of nucleotides, but PES does not. Both inhibitors significantly lower HSP70 ATPase activity and substrate protein disaggregation activity. However, KBR1307 displays a lower IC50 value at the MCF-7 cell line compared to PES. Both inhibitors do not alter HSP70 secondary structure composition and overall stability. Conclusion: KBR1307 effectively inhibits HSP70 compared to PES and provides a promising template for novel anticancer drug development.
dc.description.sponsorshipTUBITAK [114Z365COST 106076, 116Z053]
dc.description.sponsorshipThis work is supported by TUBITAK Project No: 114Z365COST 106076 for YT, and 116Z053 for IK.
dc.identifier.doi10.2174/1871520620666200918103509
dc.identifier.endpage1480
dc.identifier.issn1871-5206
dc.identifier.issn1875-5992
dc.identifier.issue11
dc.identifier.pmid32951578
dc.identifier.scopus2-s2.0-85103000640
dc.identifier.scopusqualityQ3
dc.identifier.startpage1472
dc.identifier.urihttps://doi.org/10.2174/1871520620666200918103509
dc.identifier.urihttps://hdl.handle.net/20.500.12418/30423
dc.identifier.volume21
dc.identifier.wosWOS:000634324800012
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofAnti-Cancer Agents in Medicinal Chemistry
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectPyrazole
dc.subjectcoumarine
dc.subjectHSP70 inhibitor
dc.subjectsubstrate binding domain
dc.subjectprotein folding
dc.subjectPES
dc.subjectnucleotide
dc.subjectATPase
dc.titleDesigning Specific HSP70 Substrate Binding Domain Inhibitor for Perturbing Protein Folding Pathways to Inhibit Cancer Mechanism
dc.typeArticle

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