2. Academic Validation
  3. Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol

Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol

  • Eur J Med Chem. 2022 Jun 5;236:114323. doi: 10.1016/j.ejmech.2022.114323.
Xing-Zi Li 1,  Shi-You Jiang 2,  Guo-Qiang Li 3,  Qian-Ru Jiang 1,  Jue-Wan Li 4,  Chen-Chen Li 1,  Yu-Qin Han 2,  Bao-Liang Song 2,  Xin-Ran Ma 5,  Wei Qi 6,  Wen-Wei Qiu 7
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
  • 2 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 5 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: xrma@bio.ecnu.edu.cn.
  • 6 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: qiwei@shanghaitech.edu.cn.
  • 7 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
PMID: 35397399 DOI: 10.1016/j.ejmech.2022.114323
Abstract

HMG-CoA reductase (HMGCR) is the rate-limiting Enzyme in Cholesterol de novo biosynthesis and its degradation may bring therapeutic benefits for the treatment of Cardiovascular Disease (CVD) and nonalcoholic steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting Cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using a HMGCR (TM1-8)-GFP reporting system. Among them, the most active compound 29 (QH536) showed an EC50 of 0.22 μΜ in promoting HMGCR degradation, which was about 2 times more potent than HMG499 (EC50 = 0.43 μM). Interestingly, 29 was different from HMG499, it had no side-effect of inducing Cholesterol accumulation in cells. Mechanistic studies disclosed that 29 could significantly decrease statin-induced accumulation of HMGCR protein via ubiquitination and degradation of HMGCR through ubiquitin-proteasome pathway and inhibit the Cholesterol biosynthesis in cells. Therefore, these heterocyclic ring-fused analogs could be used as promising leads for the development of new types of agents against CVD. Furthermore, 29 also lowered Cholesterol levels and suppressed TGFβ1-induced proliferation of LX-2 hepatic stellate cells in a dose-dependent manner. In particular, 29 not only decreased the NASH associated fibrotic mRNA and protein expression of α-SMA, COL1A1, TIMP1 and TGFβ1 but also suppressed Cholesterol levels and inflammatory genes of TNF-α, IL-6 an IL-1β in RAW264.7 macrophage cells, indicating that 29 may bring therapeutic benefit to treat NASH.

Keywords

Cardiovascular disease; Cholesterol; Degrader; HMG-CoA reductase; NASH.

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