Discovery and Preclinical Evaluation of TPM003: A Novel GLP-1/GIP/Glucagon Triple Hormone Receptor Agonist with Robust Efficacy in Obesity and NASH

  • J Med Chem. 2026 Feb 26;69(4):4984-5001. doi: 10.1021/acs.jmedchem.5c03845.
Nan Zheng  1 ,  Longfang Tu  1 ,  Pu Xu  1 ,  Rongfang Chen  1 ,  Jiang Lu  1 ,  Wan Dai  1 ,  Yanxia Lin  1  2 ,  Jianmei Ouyang  1 ,  Jinying Qiu  1  3 ,  You Wang  1  3 ,  Leiming Wang  1 ,  Weijun Shen  1  3
Affiliations
  • 1. Translational Innovation Center, Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong, China.
  • 2. Torrey Pines Medicine Co, Ltd., Shenzhen 518132, Guangdong, China.
  • 3. Center for Translational Research, Changping Laboratory, Beijing 102206, China.
PMID: 41640214 DOI: 10.1021/acs.jmedchem.5c03845
Abstract

Harnessing the simultaneous activation of GLP-1R, GIPR, and GCGR has emerged as a highly promising therapeutic paradigm for obesity and related metabolic diseases, including nonalcoholic steatohepatitis (NASH). Here, we report the discovery of TPM003, a novel unimolecular GLP-1R/GIPR/GCGR triple agonist engineered by using a long-acting PEG-fatty acid (PEG-FA) stapling technology. TPM003 exhibits balanced triple receptor agonism and demonstrates an extended systemic half-life across multiple species. In obese mice, TPM003 induced robust and durable weight loss, accompanied by broad improvements in metabolic parameters, outperforming current GLP-1RA standards. Importantly, TPM003 also effectively reversed hepatic steatosis and improved markers of liver function in multiple NASH models. Furthermore, TPM003 is compatible with SNAC-based absorption enhancement, enabling oral delivery in a tablet formulation. Collectively, these findings highlight the therapeutic advantages of balanced GLP-1R/GIPR/GCGR agonism for obesity and NASH and support TPM003 as a promising preclinical candidate with translational potential.

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