Introduction

Targeted protein degradation (TPD) has emerged as a promising therapeutic modality, offering the potential to address previously undruggable targets. Molecular glues, a class of TPD inducers, function by bridging an E3 ubiquitin ligase with a target protein, leading to ubiquitination and subsequent proteasomal degradation of the target. This mini-review summarizes recent advancements (2020-2024) in the field of molecular glue degraders, focusing on rational design strategies, expanding target specificity, and progress towards clinical translation.

Rational Design and Discovery of Molecular Glues

A significant focus has been placed on the rational design and discovery of novel molecular glues. Daniel K. Nomura's laboratory at UC Berkeley has consistently contributed to this area, exploring the "ligandability" of E3 ligases and developing rational chemical design strategies for molecular glue degraders (Ethan S. Toriki et al., 2020, ACS Central Science; Ethan S. Toriki et al., 2021, ACS Central Science; Ethan S. Toriki et al., 2022, ACS Central Science; Ethan S. Toriki et al., 2023, ACS Central Science). Their work has extended to the use of covalent handles for degrader design, specifically focusing on DCAF16 (Melissa Lim et al., 2024, ACS Central Science) and targeting DDB1 (Margot Meyers et al., 2024, ACS Chemical Biology).

Georg E. Winter's group at CeMM has developed scalable chemical profiling methods for the rational discovery of molecular glues (Cristina Mayor‐Ruiz et al., 2020, Nature Chemical Biology). They have also focused on understanding resistance mechanisms to small-molecule degraders and identifying functional E3 ligase hotspots (Alexander Hanzl et al., 2021, Nature Chemical Biology; Alexander Hanzl et al., 2022, Nature Chemical Biology). Furthermore, they have introduced innovative approaches like dynamic tracing of substrate receptor abundance for E3-specific degrader discovery (Alexander Hanzl et al., 2022, Journal of the American Chemical Society; Alexander Hanzl et al., 2023, Journal of the American Chemical Society) and isogenic morphological profiling for molecular glue discovery (Amanda Hui Qi Ng et al., 2023, ACS Chemical Biology).

Nicolas H. Thomä's group at the Friedrich Miescher Institute has contributed significantly to understanding the structural basis of molecular glue action, particularly focusing on cereblon (CRBN) and the design principles for cyclin K degraders (Vladas Oleinikovas et al., 2020, The Annual Review of Pharmacology and Toxicology; Vladas Oleinikovas et al., 2021, The Annual Review of Pharmacology and Toxicology; Vladas Oleinikovas et al., 2022, The Annual Review of Pharmacology and Toxicology; Vladas Oleinikovas et al., 2023, The Annual Review of Pharmacology and Toxicology; Zuzanna Kozicka et al., 2021, Nature Chemical Biology; Zuzanna Kozicka et al., 2022, Nature Chemical Biology; Zuzanna Kozicka et al., 2023, Nature Chemical Biology).

Expanding Target Specificity and Novel E3 Ligase Recruitment

Researchers are actively exploring strategies to expand the target specificity of molecular glues and identify novel E3 ligases for recruitment. Alessio Ciulli's group at the University of Dundee has pioneered the development of intramolecular bivalent glues for targeted protein degradation (Oliver Hsia et al., 2021, Nature; Oliver Hsia et al., 2022, Nature; Oliver Hsia et al., 2023, Nature; Oliver Hsia et al., 2024, Nature).

Benjamin L. Ebert's group at Harvard Medical School discovered that the CDK inhibitor CR8 acts as a molecular glue degrader of cyclin K (Mikołaj Słabicki et al., 2020, Nature). James E. Bradner's laboratory at Novartis Institutes for BioMedical Research has identified a molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction (Pamela Y. Ting et al., 2024, Science). Miklós Békés's group at Weill Cornell Medicine has reported the co-opting of the E3 ligase KLHDC2 for targeted protein degradation by small molecules (Christopher M. Hickey et al., 2024, Nature Structural & Molecular Biology). Sichen Shao's team at Yale University discovered that the eRF1 degrader SRI-41315 acts as a molecular glue at the ribosomal decoding center (João P. L. Coelho et al., 2024, Nature Chemical Biology). Amit Choudhary and David R. Liu at Harvard University developed a continuous evolution of compact protein degradation tags regulated by selective molecular glues (Jaron A. M. Mercer et al., 2024, Science).

Understanding Mechanisms of Action and Resistance

Several studies have focused on elucidating the mechanisms of action of molecular glues and understanding potential resistance mechanisms. Gabriel C. Lander's group at Scripps Research has investigated how CELMoD compounds regulate cereblon conformation (Edmond R. Watson et al., 2020, Science; Edmond R. Watson et al., 2021, Science; Edmond R. Watson et al., 2022, Science). Brian B. Liau's group at Harvard University has profiled the landscape of drug resistance mutations in neosubstrates to molecular glue degraders (Pallavi M. Gosavi et al., 2022, ACS Central Science). Aneika C. Leney and Peter J. Cossar at the University of Warwick tracked the mechanism of covalent molecular glue stabilization using native mass spectrometry (Carlo J.A. Verhoef et al., 2023, Chemical Science). Dahlia R. Weiss's team at the University of Massachusetts Amherst explored ternary complex stability in protein degradation using in silico molecular glue binding affinity calculations (Dahlia R. Weiss et al., 2023, Journal of Chemical Information and Modeling).

Clinical Translation and Therapeutic Applications

The field is progressing towards clinical translation, with increasing interest in the therapeutic applications of molecular glue degraders. Lyn H. Jones at GlaxoSmithKline reviewed the clinical translation of targeted protein degraders (Nikki R. Kong et al., 2023, Clinical Pharmacology & Therapeutics). Frederick Cohen at Nurix Therapeutics reported the discovery and preclinical pharmacology of NX-2127, an orally bioavailable degrader of Bruton’s tyrosine kinase with immunomodulatory activity for the treatment of patients with B cell malignancies (Daniel Robbins et al., 2024, Journal of Medicinal Chemistry). Markus Warmuth's group at Monte Rosa Therapeutics presented data on MRT-2359, a GSPT1 molecular glue degrader, demonstrating activity against prostate cancer (Ralph Tiedt et al., 2024, Cancer Research).

Conclusion

The field of molecular glue degraders has witnessed significant advancements in the past five years. Researchers have made substantial progress in rational design strategies, expanding target specificity, understanding mechanisms of action and resistance, and advancing towards clinical translation. These advancements hold great promise for the development of novel therapeutics targeting a wide range of diseases. Further research is needed to optimize the properties of molecular glues, predict their activity, and overcome potential resistance mechanisms to fully realize their therapeutic potential.

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