2. Academic Validation
  3. Discovery of N-Aryl- N'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation

Discovery of N-Aryl- N'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation

  • J Med Chem. 2024 Oct 10;67(19):17608-17628. doi: 10.1021/acs.jmedchem.4c01597.
Long Huu Nguyen 1,  Ye Eun Cho 1,  Soyeong Kim 1 2,  Yeonsoo Kim 1,  Jinsook Kwak 1,  Jung-Soo Suh 3,  Jinyoung Lee 1,  Kyuwon Son 1,  Minseong Kim 1,  Eun Seo Jang 1,  Naghyun Song 1,  BuChul Choi 1,  Jiah Kim 1,  Yealin Tak 1,  Taeyeon Hwang 4,  Jeyun Jo 1,  Eun-Woo Lee 5,  Sang-Bum Kim 2,  Sanghyun Kim 6,  Oh-Bin Kwon 2,  Sangok Kim 4,  Seoung Rak Lee 1 7,  Haeseung Lee 1 7,  Tae-Jin Kim 3,  Seonghwan Hwang 1 7,  Hwayoung Yun 1 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
  • 2 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
  • 3 Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea.
  • 4 Korea Bioinformation Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon 34141, Republic of Korea.
  • 5 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
  • 6 Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.
  • 7 Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.
PMID: 39259827 DOI: 10.1021/acs.jmedchem.4c01597
Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound 31 was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis. Further investigation revealed that compound 31 may indirectly inhibit the LXR/SREBP-1c pathway by activating the upstream regulator Sirtuin 6 (SIRT6). Encouragingly, compound 31 substantially attenuated lipid accumulation in HepG2 cells and in the liver of high-fat-diet-fed mice. These findings suggest that compound 31 holds promise as a candidate for the development of treatments for MASLD and Other lipid metabolism-related diseases.

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