Haven't got a glue: Protein surface variation for the design of molecular glue degraders

Kozicka, Zuzanna; Thomä, Nicolas H.

doi:10.1016/j.chembiol.2021.04.009

Cited by 95 publications

(90 citation statements)

References 103 publications

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“…For example, the very successful drug Revlimid (lenalidomide, which is a small molecule molecular glue compound) binds to at least 13 functional proteins. 86 However, toxicity was not an issue for Revlimid in its approval by the FDA for the treatment of multiple myeloma. In this regard, a molecular glue compound having multiple targets may be an advantage, instead of a weakness, for the compound to exhibit high antitumour activity.…”

Section: Discussionmentioning

confidence: 99%

FL118, acting as a ‘molecular glue degrader’, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c‐Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy

Ling

Aljahdali

et al. 2022

Clinical & Translational Med

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By acting as a 'molecular glue degrader', FL118 directly binds to and functionally dephosphorylates and degrades the multifunctional master regulator DDX5 through the proteasome degradation pathway without decreasing DDX5 mRNA.• FL118 indirectly controls DDX5 downstream targets to inhibit cancer initiation, development, metastasis, recurrence and treatment resistance with high efficacy as demonstrated in this study using human colorectal cancer/pancreatic ductal adenocarcinoma cell and tumour models.

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Section: Discussionmentioning

confidence: 99%

FL118, acting as a ‘molecular glue degrader’, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c‐Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy

Ling

Aljahdali

et al. 2022

Clinical & Translational Med

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“…There are many excellent review articles that have systematically reviewed the key findings related to molecular glue (MG) for MG-targeted protein degradation, among others [ 2 , 9 , 12 ]. Our goal in this review is to emphasize various mechanistic working models while avoiding detailed mechanistic information.…”

Section: Molecular Glues For Cancer Treatmentmentioning

confidence: 99%

“…It has been reported that the CRL4 CRBN complex E3 ligase can be used by the small-molecule MG of thalidomide and its structural analogs (lenalidomide/Revlimid, pomalidomide, avadomide, 5-hydroxythalidomide, FPFT-2216, CC-647, CC-3060, iberdomide, mezigdomide, CC-885, eragidomide, and ZXH-1-161) to ubiquitinate the MG-recruited/bound protein neosubstrates ( Table 1 ), and these have been well-reviewed recently [ 12 ] ( Figure 1 A,B). However, based on the literature-documented studies, one interesting phenomenon that may be worthy of emphasis is that thalidomide and its individual analogs with different chemical structures can share the same CRL4 CRBN complex E3 ligase for ubiquitinating different protein neosubstrates glued by them.…”

Section: Molecular Glues For Cancer Treatmentmentioning

confidence: 99%

“…To keep the review article relatively succinct, we focus on elucidating different working models without describing the detailed molecular interaction mechanism including the binding ternary interface residue contacts in individual working models. For such ternary interface interaction details, readers could refer to recent review articles [ 9 , 12 ]. In this way, we can let our classified models fit broader research.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Aljahdali

Ling

2022

IJMS

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Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Evidence suggests that small-molecule MG compounds could essentially target any proteins, which play critical roles in human disease etiology, where many of these protein targets were previously considered undruggable. Intriguingly, most MG compounds with high efficacy for cancer treatment can glue on and control multiple key protein targets. On the other hand, a single key protein target can also be glued by multiple MG compounds with distinct chemical structures. The high flexibility of MG–protein interaction profiles provides rich soil for the growth and development of small-molecule MG compounds that can be used as molecular tools to assist in unraveling disease mechanisms, and they can also facilitate drug development for the treatment of human disease, especially human cancer. In this review, we elucidate this concept by using various types of small-molecule MG compounds and their corresponding protein targets that have been documented in the literature.

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“…While naturally occurring substrate recognition is evolutionary optimized, small-molecule degraders often induce and stabilize the formation of de novo protein-protein interactions 2,8,9 . As a result, degraders rely on an optimal exploitation of the structural plasticity of both involved protein surfaces and leveraging PPI energetics from the induced proximity.…”

Section: Introductionmentioning

confidence: 99%

Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

Hanzl

Casement

Imrichová

et al. 2022

Preprint

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Targeted protein degradation is a new pharmacologic paradigm established by drugs that recruit target proteins to E3 ubiquitin ligases via a ternary ligase-degrader-target complex. Based on the structure of the degrader and the neosubstrate, different E3 ligase interfaces are critically involved in this process, thus forming defined functional hotspots. Understanding disruptive mutations in functional hotspots informs on the architecture of the underlying assembly, and highlights residues prone to cause drug resistance. Until now, their identification was driven by structural methods with limited scalability. Here, we employ haploid genetics to show that hotspot mutations cluster in the substrate receptors of the hijacked ligases and find that type and frequency of mutations are shaped by the essentiality of the harnessed ligase. Intersection with deep mutational scanning data revealed hotspots that are either conserved, or specific for chemically distinct degraders or recruited neosubstrates. Biophysical and structural validation suggest that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we identified and validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and experimentally widely accessible methodology that empowers the characterization of small-molecule degraders and informs on associated resistance mechanisms.

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Haven't got a glue: Protein surface variation for the design of molecular glue degraders

Cited by 95 publications

References 103 publications

FL118, acting as a ‘molecular glue degrader’, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c‐Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy

FL118, acting as a ‘molecular glue degrader’, binds to, dephosphorylates and degrades the oncoprotein DDX5 (p68) to control c‐Myc, survivin and mutant Kras against colorectal and pancreatic cancer with high efficacy

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

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