Applications of covalent chemistry in targeted protein degradation

Lu, Dong; Yu, Xin; Lin, Hanfeng; Cheng, Ran; Monroy, Erika Y.; Qi, Xiaoli; Wang, Meng C.

doi:10.1039/d2cs00362g

Cited by 22 publications

(15 citation statements)

References 143 publications

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“…In our current study, we demonstrate that the addition of electrophiles to the solvent-exposed side of JQ1, results in DCAF16-dependent covalent molecular glue degraders. The addition of electrophilic warheads to protein binders could become an effective strategy to stabilize a ternary complex and enable protein degradation when similar non-covalent molecules do not 39 . We envision that template-assisted covalent modification strategies can be exploited to facilitate future rational design and discovery of molecular glue degraders.…”

Section: Discussionmentioning

confidence: 99%

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Michelle

Hassan

et al. 2023

Preprint

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Small molecules that induce protein-protein interactions to exert proximity-driven pharmacology such as targeted protein degradation are a powerful class of therapeutics. Molecular glues are of particular interest given their favorable size and chemical properties and represent the only clinically approved degrader drugs. The discovery and development of molecular glues for novel targets, however, remains challenging. Covalent strategies could in principle facilitate molecular glue discovery by stabilizing the neo-protein interfaces. Here, we present structural and mechanistic studies that define a trans-labeling covalent molecular glue mechanism, which we term "template-assisted covalent modification". We found that a novel series of BRD4 molecular glue degraders act by recruiting the CUL4DCAF16 ligase to the second bromodomain of BRD4 (BRD4BD2). BRD4BD2, in complex with DCAF16, serves as a structural template to facilitate covalent modification of DCAF16, which stabilizes the BRD4-degrader-DCAF16 ternary complex formation and facilitates BRD4 degradation. A 2.2 A cryo-electron microscopy structure of the ternary complex demonstrates that DCAF16 and BRD4BD2 have pre-existing structural complementarity which optimally orients the reactive moiety of the degrader for DCAF16 Cys58 covalent modification. Systematic mutagenesis of both DCAF16 and BRD4BD2 revealed that the loop conformation around BRD4 His437, rather than specific side chains, is critical for stable interaction with DCAF16 and BD2 selectivity. Together our work establishes "template-assisted covalent modification" as a mechanism for covalent molecular glues, which opens a new path to proximity driven pharmacology.

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Section: Discussionmentioning

confidence: 99%

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Michelle

Hassan

et al. 2023

Preprint

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“…145 These warheads have also been utilized in the development of reversible covalent PROTACs, such as RC-1 ( 54 ), which facilitate effective inhibition and catalytic degradation of BTK in mice. 146,147…”

Section: Chemical Toolbox For Small-molecule Probesmentioning

confidence: 99%

Small-molecule probes from bench to bedside: advancing molecular analysis of drug–target interactions toward precision medicine

Pan

Ding

et al. 2023

Chem. Soc. Rev.

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“…Most early work focused on degradation through inducing proximity to enable ubiquitination. In this context, covalently binding degraders are considered to be more efficacious. , Also, many of the approaches, that we presented in this Perspective on heterobifunctional degraders, can be applied to the characterization of molecular glues, which, however, presents its own set of challenges, such as the screening for suitable chemical matter or the identification of an appropriate E3 ligase for a given target POI. Moreover, we are now seeing the surfacing of many other modes of degradation, such as lysosome-targeting chimeras (LYTACs), macroautophagy degradation targeting chimeras (MADTACs), autophagy-targeting chimeras (AUTOTACs), deubiquitinase-targeting chimeras (DUBTACs), and chaperone-mediated protein degraders (CHAMPs).…”

Section: Future Directionsmentioning

confidence: 99%

Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

Mostofian,

Martin,

Razavi

et al. 2023

J. Chem. Inf. Model.

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The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods. TPD involves creating a ternary structure (protein−degrader−ligase) responsible for the biological function, such as ubiquitination and subsequent proteasomal degradation, which depends on the spatial orientation of the protein of interest (POI) relative to E2-loaded ubiquitin. Modeling this structure necessitates a unique blend of tools initially developed for small molecules (e.g., docking) and biologics (e.g., protein−protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, are generally larger than conventional small molecule drugs, leading to challenges in determining drug-like properties like solubility and permeability. Furthermore, the catalytic nature of TPD makes occupancy-based modeling insufficient. TPD consists of multiple interconnected yet distinct steps, such as POI binding, E3 ligase binding, ternary structure interactions, ubiquitination, and degradation, along with traditional small molecule properties. A comprehensive set of tools is needed to address the dynamic nature of the induced proximity ternary complex and its implications for ubiquitination. In this Perspective, we discuss the current state of computational tools for TPD. We start by describing the series of steps involved in the degradation process and the experimental methods used to characterize them. Then, we delve into a detailed analysis of the computational tools employed in TPD. We also present an integrative approach that has proven successful for degrader design and its impact on project decisions. Finally, we examine the future prospects of computational methods in TPD and the areas with the greatest potential for impact.

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Applications of covalent chemistry in targeted protein degradation

Abstract: This review summarizes the recent work of covalent chemistry in targeted protein degradation and describes the concept, pros and cons, development, and the outlook of covalent PROTACs.

Cited by 22 publications

References 143 publications

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders

Small-molecule probes from bench to bedside: advancing molecular analysis of drug–target interactions toward precision medicine

Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

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