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  • Iqbal, ShaziaTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye (author)

Design and synthesis of novel JNK inhibitors targeting liver pyruvate kinase for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Elsevier BV,2024
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-346508
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-346508URI
  • https://doi.org/10.1016/j.bioorg.2024.107425DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20240520
  • Non-alcoholic fatty liver disease (NAFLD) comprises a broad range of liver disease including hepatocellular carcinoma (HCC) with is no FDA-approved drug. Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP generation in liver presenting a potential target for the treatment of NAFLD. Based on our recent finding of JNK-5A's effectiveness in inhibiting PKLR expression through a drug repositioning pipeline, this study aims to improve its efficacy further. We synthesized a series of JNK-5A analogues with targeted modifications, guided by molecular docking studies. These compounds were evaluated for their activities on PKL expression, cell viability, triacylglyceride (TAG) levels, and the expressions of steatosis-related proteins in the human HepG2 cell line. Subsequently, the efficacy of these compounds was assessed in reducing TAG level and toxicity. Compounds 40 (SET-151) and 41 (SET-152) proved to be the most efficient in reducing TAG levels (11.51 ± 0.90 % and 10.77 ± 0.67 %) and demonstrated lower toxicity (61.60 ± 5.00 % and 43.87 ± 1.42 %) in HepG2 cells. Additionally, all synthesized compounds were evaluated for their anti-cancer properties revealing that compound 74 (SET-171) exhibited the highest toxicity in cell viability with IC50 values of 8.82 µM and 2.97 µM in HepG2 and Huh7 cell lines, respectively. To summarize, compounds 40 (SET-151) and 41 (SET-152) show potential for treating NAFLD, while compound 74 (SET-171) holds potential for HCC therapy.

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  • Sebhaoui, JihadTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye; Life and Health Sciences Laboratory, Faculty of Medicine and Pharmacy of Tangier, Abdelmalek Essaadi University, Morocco (author)
  • Ashraf, SajdaTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye (author)
  • Özcan, MehmetKTH,Science for Life Laboratory, SciLifeLab,Department of Medical Biochemistry, Faculty of Medicine, Zonguldak Bulent Ecevit University, Zonguldak, Turkiye(Swepub:kth)u1ilte0b (author)
  • Kim, WoongheeKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1nic2pk (author)
  • Belmen, BurcuTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye (author)
  • Yeşilyurt, GüldenizTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye (author)
  • Hanashalshahaby, EssamTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye (author)
  • Zhang, ChengKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1ww5kvp (author)
  • Uhlén, MathiasKTH,Systembiologi,Science for Life Laboratory, SciLifeLab(Swepub:kth)u1dulvmw (author)
  • Boren, JanDepartment of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden (author)
  • Turkez, HasanDepartment of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkiye (author)
  • Mardinoglu, AdilKTH,Systembiologi,Science for Life Laboratory, SciLifeLab,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK(Swepub:kth)u1t8kmr6 (author)
  • Trustlife Labs Drug Research & Development Center, 34774 Istanbul, TurkiyeTrustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye; Life and Health Sciences Laboratory, Faculty of Medicine and Pharmacy of Tangier, Abdelmalek Essaadi University, Morocco (creator_code:org_t)

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  • In:Bioorganic chemistry: Elsevier BV1470045-2068

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