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

Chang Shen¹, Hanyin Sun¹, Ruining Li¹

¹Shanghai 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.

Journal of Medicinal Chemistry

|July 8, 2026

Summary

New RIPK1-Mediated Targeting Chimeras (RIMTACs) expand targeted protein degradation (TPD) tools. RIMTACs indirectly recruit E3 ligases, enabling degradation of targets like BRD4, AKT, and JAK1 for potential anti-inflammatory therapies.

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Area of Science:

Biochemistry
Molecular Biology
Drug Discovery

Background:

Proteolysis-targeting chimeras (PROTACs) are a key technology for targeted protein degradation (TPD).
The therapeutic application of PROTACs is constrained by a limited selection of E3 ligase ligands, with only a small subset of the over 600 human E3 ligases being currently usable.
Developing novel strategies to broaden the E3 ligase repertoire is crucial for advancing TPD therapeutics.

Purpose of the Study:

To introduce a novel TPD strategy, RIPK1-Mediated Targeting Chimeras (RIMTACs), to overcome the limitations of existing E3 ligase ligands.
To demonstrate the efficacy of RIMTACs in degrading specific target proteins, including BRD4, AKT, and JAK1.
To explore the potential of RIMTACs as a synergistic approach for anti-inflammatory therapies.

Main Methods:

Development of RIMTACs, which utilize a RIPK1 inhibitor to indirectly engage the endogenous RIPK1-VHL complex for TPD.
Design and synthesis of RIMTAC molecules targeting BRD4, AKT, and JAK1.
Assessment of target protein degradation using concentration- and time-dependent assays, confirming UPS-dependence and the formation of a quaternary complex.

Main Results:

RIMTACs were successfully designed and demonstrated to induce potent, concentration- and time-dependent degradation of BRD4, AKT, and JAK1.
The mechanism of degradation was confirmed to be ubiquitin-proteasome system (UPS)-dependent.
Degradation necessitates the formation of a specific quaternary complex involving VHL, RIPK1, the target protein, and the RIMTAC molecule.

Conclusions:

RIMTACs represent a novel and effective expansion of the TPD toolbox, offering an alternative to direct E3 ligase recruitment.
This approach successfully hijacks endogenous complexes to achieve targeted protein degradation.
RIMTACs show promise as a synergistic strategy for developing novel anti-inflammatory therapies.