Proximity-inducing modalities: the past, present, and future

Singh, Sameek; Tian, Wenzhi; Severance, Zachary C; Chaudhary, Santosh Kumar; Anokhina, Viktoriya; Mondal, Basudeb; Pergu, Rajaiah; Singh, Prashant Kumar; Dhawa, Uttam; Singha, Santanu; Choudhary, Amit

doi:10.1039/d2cs00943a

Cited by 9 publications

(12 citation statements)

References 286 publications

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“…Crucially, the presented experimental and analytical strategy could be adapted to identify proximity-inducing compounds outside the field of targeted protein degradation, which is an active area of research. , Here we focus on targeted protein degradation. Following our focus, we employed quantitative proteomics for the initial target/mechanistic elucidation for hit compounds identified by the isogenic CPA.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

Ng,

Offensperger,

Cisneros

et al. 2023

ACS Chem. Biol.

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Molecular glue degraders (MGDs) are small molecules that degrade proteins of interest via the ubiquitin–proteasome system. While MGDs were historically discovered serendipitously, approaches for MGD discovery now include cell-viability-based drug screens or data mining of public transcriptomics and drug response datasets. These approaches, however, have target spaces restricted to the essential proteins. Here we develop a high-throughput workflow for MGD discovery that also reaches the nonessential proteome. This workflow begins with the rapid synthesis of a compound library by sulfur(VI) fluoride exchange chemistry coupled to a morphological profiling assay in isogenic cell lines that vary in levels of the E3 ligase CRBN. By comparing the morphological changes induced by compound treatment across the isogenic cell lines, we were able to identify FL2-14 as a CRBN-dependent MGD targeting the nonessential protein GSPT2. We envision that this workflow would contribute to the discovery and characterization of MGDs that target a wider range of proteins.

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Section: Discussionmentioning

confidence: 99%

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

Ng,

Offensperger,

Cisneros

et al. 2023

ACS Chem. Biol.

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“…3 Proximity between two proteins A and B can be either be induced by a compound which relies upon high binary potency to both proteins, or by a compound which, upon binding to protein A, induces a neosurface on protein A which favours binding of the two proteins A and B to one another. 4 The difference between these two categories of CIP is described by the cooperativity (a) of the interactions between the compound and the two proteins in the complex. Cooperativity is calculated by dividing the K D of the binary binding by the K D of the ternary binding (Fig.…”

Section: Introduction and Traditional Synthetic Approaches To Degradersmentioning

confidence: 99%

“…Further details on the mechanisms behind these proximity inducing molecules have been the focus of several other reviews. 2,4,5 Whilst CIPs can recruit a range of different effectors to a POI, this review will focus specifically on POI degraders.…”

Section: Introduction and Traditional Synthetic Approaches To Degradersmentioning

confidence: 99%

Innovative, combinatorial and high-throughput approaches to degrader synthesis

Stevens,

Thompson,

Fournier

et al. 2024

Chem. Soc. Rev.

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“…Several bifunctional “proximity-inducing” , therapeutic strategies function through the highly stabilized engagement of carbohydrate binding receptors. One strategy uses lysosome targeting chimeras (LYTACs), which integrate a tumor-targeting antibody with a multivalent array of GalNac and M6Pn sugars. , The simultaneous engagement of ASGPR or CI-M6PR and the target leads to endocytosis and lysosome accumulation/degradation of the cell surface or soluble target proteins.…”

Section: Introductionmentioning

confidence: 99%

“…18−21 For example, the PPV23 vaccine induces anticarbohydrate antibodies to protect against a variety of streptococcus pneumonia serotypes (e.g., induction of α-L-rhamnose specific antibodies recognizing the 23F serotype). 22−24 This article is licensed under CC-BY 4 Several bifunctional "proximity-inducing" 25,26 therapeutic strategies function through the highly stabilized engagement of carbohydrate binding receptors. One strategy uses lysosome targeting chimeras (LYTACs), which integrate a tumortargeting antibody with a multivalent array of GalNac and M6Pn sugars.…”

Section: ■ Introductionmentioning

confidence: 99%

Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction

Lake,

Rullo

2023

ACS Cent. Sci.

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Carbohydrate-binding receptors are often used by the innate immune system to potentiate inflammation, target endocytosis/destruction, and adaptive immunity (e.g., CD206, DC-SIGN, MBL, and anticarbohydrate antibodies). To access this class of receptors for cancer immunotherapy, a growing repertoire of bifunctional proximity-inducing therapeutics use high-avidity multivalent carbohydrate binding domains to offset the intrinsically low affinity associated with monomeric carbohydrate−protein binding interactions (K d ≈ 10 −3 −10 −6 M). For applications aimed at recruiting anticarbohydrate antibodies to tumor cells, large synthetic scaffolds are used that contain both a tumor-binding domain (TBD) and a multivalent antibody-binding domain (ABD) comprising multiple L-rhamnose monosaccharides. This allows for stable bridging between tumor cells and antibodies, which activates tumoricidal immune function. Problematically, such multivalent macromolecules can face limitations including synthetic and/or structural complexity and the potential for off-target immune engagement. We envisioned that small bifunctional "proximity-inducing" molecules containing a low-affinity monovalent ABD could efficiently engage carbohydrate-binding receptors for tumor-immune proximity by coupling weak binding with covalent engagement. Typical covalent drugs and electrophilic chimeras use high-affinity ligands to promote the fast covalent engagement of target proteins (i.e., large k inact /K I ), driven by a favorably small K I for binding. We hypothesized the much less favorable K I associated with carbohydrate−protein binding interactions can be offset by a favorably large k inact for the covalent labeling step. In the current study, we test this hypothesis in the context of a model system that uses rhamnose-specific antibodies to induce tumor-immune proximity and tumoricidal function. We discovered that synthetic chimeric molecules capable of preorganizing an optimal electrophile (i.e., SuFEx vs activated ester) for protein engagement can rapidly covalently engage natural sources of antirhamnose antibody using only a single low-affinity rhamnose monosaccharide ABD. Strikingly, we observe chimeric molecules lacking an electrophile, which can only noncovalently bind the antibody, completely lack tumoricidal function. This is in stark contrast to previous work targeting small molecule hapten and peptide-specific antibodies. Our findings underscore the utility of covalency as a strategy to engage low-affinity carbohydrate-specific proteins for tumor-immune proximity induction.

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Proximity-inducing modalities: the past, present, and future

Abstract: In this review, we highlight bifunctional modalities that perform functions other than degradation and have great potential to revolutionize disease treatment, while also serving as important tools in basic research to explore new aspects of biology.

Cited by 9 publications

References 286 publications

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

Innovative, combinatorial and high-throughput approaches to degrader synthesis

Offsetting Low-Affinity Carbohydrate Binding with Covalency to Engage Sugar-Specific Proteins for Tumor-Immune Proximity Induction

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