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
  • 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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