2. Academic Validation
  3. Discovery of 8-quinolinesulfonamide phenylimidazole-based PKM2 agonists for the prevention and delay of aortic dissection

Discovery of 8-quinolinesulfonamide phenylimidazole-based PKM2 agonists for the prevention and delay of aortic dissection

  • Eur J Med Chem. 2025 Dec 13:304:118479. doi: 10.1016/j.ejmech.2025.118479.
Junda Li 1,  Yanyan Yang 2,  Lei Cheng 1,  Xu Xu 1,  Ke Zhong 2,  Tao Wang 1,  Kailin Chen 1,  Chi Zhang 1,  Chen He 1,  Jinyi Xu 3,  Shengtao Xu 4,  Shanshan Luo 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China.
  • 2 Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China.
  • 3 Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: jinyixu@china.com.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address: cpuxst@163.com.
  • 5 Key Laboratory of Drug Targets and Translational Medicine for Cardio-cerebrovascular Diseases; Key Laboratory of Targeted Intervention of Cardiovascular Disease; Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China. Electronic address: njmulss@njmu.edu.cn.
PMID: 41420891 DOI: 10.1016/j.ejmech.2025.118479
Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular condition with a poor prognosis and high mortality rate. Currently, no specific pharmacological therapies are available for TAAD prevention. Clinical management depends mainly on antihypertensive drugs to reduce blood pressure and the risk of aortic rupture, supplemented by surgical intervention when necessary. In this study, guided by structural analysis of known PKM2 agonists and retention of key pharmacophoric features, we initially identified a promising lead compound A2 via fragment-based virtual screening. Through subsequent structure-activity relationship (SAR) optimization, we designed and synthesized 77 novel derivatives, among which, compound D16 emerged as a highly effective PKM2 agonist, demonstrating potent agonist activity (AC50 = 77 nM, Emax = 216 %). D16 significantly suppressed the phenotypic switching of smooth muscle cells without apparent cytotoxicity. Furthermore, in a β-aminopropionitrile (BAPN)-induced TAAD mouse model, D16 treatment effectively prevented aortic dissection and resulted in reduced mortality compared with the approved drug Mitapivat. These results identify D16 as a promising and safe candidate for the prevention of TAAD, supporting its further investigation.

Keywords

Fragment-based virtual screening; PKM2; Small-molecule kinase agonists; TAAD.

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