RIMTAC: A Novel Degrader Design Platform by Indirect VHL-Recruitment via RIPK1

  • J Med Chem. 2026 Jul 23;69(14):17093-17117. doi: 10.1021/acs.jmedchem.6c00897.
Chang Shen  1 ,  Hanyin Sun  1 ,  Ruining Li  1 ,  Raghupathi Mutyala  1 ,  Xinjian Tian  2 ,  Chaoqun Huang  2 ,  Jinglei Hu  1 ,  Jie An  3 ,  Lin Li  1 ,  Tao Zhang  3 ,  Xufen Yu  2 ,  Bo Zhao  1 ,  Mingyan Zhu  1 ,  Yudao Shen  1  4
Affiliations
  • 1. Shanghai Frontiers Science Center of Targeted Drugs, State Key Laboratory of Innovative Immunotherapy, Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Key Laboratory for Antibody-Drug Conjugates with Innovative Target, Engineering Research Center of Cell & Therapeutic Antibody Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. School of Pharmaceutical Sciences, Key Laboratory of Smart Drug Delivery (Ministry of Education), MOE Innovative Center for New Drug Development of Immune Inflammatory Diseases, Fudan University, Shanghai 201203, China.
  • 3. Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 4. Central Research Institute, State Key Laboratory of Innovative Immunotherapy Shanghai Pharmaceuticals Holding Co., Ltd., Shanghai 201203, China.
PMID: 42417401 DOI: 10.1021/acs.jmedchem.6c00897
Abstract

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach for targeted protein degradation (TPD). However, their therapeutic potential is limited by the scarcity of diverse E3 Ligase ligands. Only a small fraction of more than 600 human E3 Ligases are currently amenable to functional PROTAC development. To expand the E3 Ligase toolbox, we developed RIPK1-Mediated Targeting Chimeras (RIMTAC). Rather than directly inhibiting VHL, RIMTAC employs a RIPK1 Inhibitor to hijack the endogenous RIPK1-VHL complex, recruiting VHL indirectly for TPD. As a proof of concept, we designed RIMTACs targeting BRD4, Akt, and JAK1. These molecules induced potent, concentration- and time-dependent degradation of their targets. Mechanistically, degradation was confirmed to be UPS-dependent and required a quaternary complex of VHL, RIPK1, the target protein, and the RIMTAC molecule. RIMTAC expands the TPD toolbox and offers a promising synergistic strategy for anti-inflammatory therapy.

Products