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Review
. 2023 Feb 7;62(3):601-623.
doi: 10.1021/acs.biochem.2c00245. Epub 2022 Jul 20.

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic

Janet M Sasso  1 , Rumiana Tenchov  1 , DaSheng Wang  1 , Linda S Johnson  1 , Xinmei Wang  1 , Qiongqiong Angela Zhou  1
Affiliations
Review

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic

Janet M Sasso et al. Biochemistry. .

Abstract

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential for treating diseases such as cancer and infectious, inflammatory, and neurodegenerative diseases, especially for those with "undruggable" pathogenic protein targets. With the recent rise of the "molecular glue" type of protein degraders, which tighten and simplify the connection of an E3 ligase with a disease-causing protein for ubiquitination and subsequent degradation, new therapies for unmet medical needs are being designed and developed. Here we use data from the CAS Content Collection and the publication landscape of recent research on targeted protein degraders to provide insights into these molecules, with a special focus on molecular glues. We also outline the advantages of the molecular glues and summarize the advances in drug discovery practices for molecular glue degraders. We further provide a thorough review of drug candidates in targeted protein degradation through E3 ligase recruitment. Finally, we highlight the progression of molecular glues in drug discovery pipelines and their targeted diseases. Overall, our paper provides a comprehensive reference to support the future development of molecular glues in medicine.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Timeline of major targeted protein degrader research and development milestones.
Figure 2
Figure 2
Schematic presentation of the degradation of a protein of interest (POI) via the ubiquitin (Ub)–proteasome system using (A) a molecular glue or (B) a PROTAC bound to the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (CRL4CRBN) complex.
Figure 3
Figure 3
Trends in the number of publications related to protein degraders in the past decade, including journal articles and patents.
Figure 4
Figure 4
Top (A) countries, (B) organizations, and (D) scientific journals publishing TPD-related journal articles and (C) top countries filing TPD-related patents.
Figure 5
Figure 5
Classes of substances represented in the TPD-related documents (left) and their role indicators according to the CAS Content Collection (right) [SPN, synthetic preparation; RCT, reactant; THU, therapeutic use; PAC, pharmacological activity; BSU, biological study (unclassified); PRP, properties].
Figure 6
Figure 6
Distribution of the protein degrader-related publications in the CAS Content Collection with respect to the target diseases.
Figure 7
Figure 7
Correlation of the number of protein degrader-related publications in the CAS Content Collection for the three most widely used E3 ligases with the targeted diseases. Percentages are from the total number of protein degrader-related publications.
Figure 8
Figure 8
(A) Number of publications presenting key concepts related to TPDs during the years 2017–2021. (B) Trends in key concepts presented in the articles related to TPDs during the years 2017–2021. Percentages are calculated with yearly publication numbers for each key concept, normalized by the total number of publications for the same concept in the same time period.
Figure 9
Figure 9
Scheme of interactions of thalidomide with CRBN (Gallus gallus). Hydrophobic interactions are depicted as orange semicircles, and hydrogen bonding is depicted as blue lines.
Figure 10
Figure 10
Number of documents in the CAS Content Collection related to E3 ligase recruiters exploited for targeted protein degradation.
Figure 11
Figure 11
Companies and research organizations with discovered molecular glues in the clinical developmental pipeline and the diseases they treat (Table S1).
See this image and copyright information in PMC

References

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