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Design and synthesis of novel JNK inhibitors targeting liver pyruvate kinase for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma
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- Iqbal, Shazia (författare)
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye
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- Sebhaoui, Jihad (författare)
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye; Life and Health Sciences Laboratory, Faculty of Medicine and Pharmacy of Tangier, Abdelmalek Essaadi University, Morocco
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- Ashraf, Sajda (författare)
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye
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- (creator_code:org_t)
- Elsevier BV, 2024
- 2024
- Engelska.
- Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 147
- Tidskriftsartikel (refereegranskat)
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
Nyckelord
- HCC
- JNK-IN-5A
- Liver pyruvate kinase
- NAFLD
- TAG level
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