Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation

Norris, Stephen; Ba, Xiaochu; Rhodes, Jayce; Huang, Dehua; Khambatta, Gody; Buenviaje, Jennifer; Nayak, Surendra; Meiring, Joseph; Reiss, Samantha; Xu, Shuichan; Shi, Lihong; Whitefield, Brandon; Alexander, Matt; Horn, Evan J.; Correa, Matthew; Tehrani, Lida; Hansen, Joshua D.; Papa, Patrick; Mortensen, Deborah S.

doi:10.1021/acs.jmedchem.3c01848

Cited by 16 publications

(14 citation statements)

References 19 publications

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“…Analysis of the structure activity landscape revealed that the high affinity compounds were predominantly derived from the sub-library of phthaloyl ring derivatives (Figure 3B). However, one indazole scaffold (Z4994098932), from the sub-library of IMiD scaffold variations, recently published to have affinity toward CRBN:DDB1 comparable to pomalidomide 23 , was also identified in this screen with very similar binding activity. (Figure 3B) (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Engineering CRBN for rapid identification of next generation binders

Bailey,

Eisert,

Vollrath

et al. 2024

Preprint

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The majority of clinical degrader candidates utilize an immunomodulatory imide drug (IMiD)-based derivative, that directs their target substrate to the E3 ligase receptor Cereblon (CRBN), however, concomitant neo-substrate degradation by IMiDs often results in severe off-target effects. Further biophysical screening is needed to discover CRBN binders that might overcome these safety concerns, but the previously reported CRBN protein constructs suffer significant limitations that reduce their applicability as tools for biophysical assays making large-scale screening efforts a costly endeavor. This is due to the requirement of CRBN co-expression with DDB1 in insect cells to produce soluble protein that contains all the reported structural features necessary for proper compound interaction. Here, a near full-length human CRBN construct was designed that retains these required features, but for the first time allows the generation of highly homogenous and cost-efficient expression in E.coli, eliminating the need for DDB1 co-expression. We have extensively profiled the new construct against the existing CRBN constructs in binary and ternary degrader complexes, showing it to be the best of both worlds in terms of binding characteristics and ease of protein production. We then designed the Enamine CRBN focused IMiD library of 4480-compounds and demonstrated applicability of the new construct to high throughput screening by identifying novel CRBN binders with high potency and ligand efficiency. The new methods described here should serve as valuable tools for the development of the next generation IMiD-based degraders.

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Section: Resultsmentioning

confidence: 99%

Engineering CRBN for rapid identification of next generation binders

Bailey,

Eisert,

Vollrath

et al. 2024

Preprint

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“…cereblon E3 ligase modulating drugs; CELMoDs) and bifunctional degraders (e.g. proteolysis targeting chimeras; PROTACs) trigger the rapid, selective degradation of targeted proteins by concurrently binding the E3 ligase and the protein targeted for degradation [6–8] . Traditional degraders possess C3(sp 3 )−N substituted glutarimides (e.g.…”

Section: Figurementioning

confidence: 99%

“…proteolysis targeting chimeras; PROTACs) trigger the rapid, selective degradation of targeted proteins by concurrently binding the E3 ligase and the protein targeted for degradation. [6][7][8] Traditional degraders possess C3(sp 3 )À N substituted glutarimides (e.g. Pomalidomide, Lenalidomide), which have proven to be valuable structural motifs for their ability to bind E3 ligase/CRBN (Figure 1A).…”

mentioning

confidence: 99%

Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross‐Coupling

Neigenfind,

Massaro,

Péter

et al. 2024

Angewandte Chemie

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C–C linked glutarimide‐containing structures with direct utility in the preparation of cereblon‐based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial a‐bromoglutarimide through a unique Brønsted‐acid assisted Ni‐electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multi‐step sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time‐consuming aspect of reaction setup is weighing out the starting materials. C–C linked glutarimide‐containing structures with direct utility in the preparation of cereblon‐based degraders (PROTACs, CELMoDs) can be assessed in a single step from inexpensive, commercial a‐bromoglutaramide through a unique Brønsted‐acid assisted Ni‐electrocatalytic approach. The reaction tolerates a broad array of functional groups that are historically problematic and can be applied to the simplified synthesis of dozens of known compounds that have only been procured through laborious, wasteful, multistep sequences. The reaction is scalable in both batch and flow and features a trivial procedure wherein the most time‐consuming aspect of reaction setup is weighing out the starting materials.

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“…Scheme 2 Key disconnections for indolinone-substituted glutarimidebased IMiDs mezigdomide (6) and iberdomide (18) The impressive kilogram-scale synthesis of iberdomide (18), which constitutes the basis for the envisioned commercial route, was recently published by Bristol Myers Squibb process chemists Zacuto and co-workers and serves as an instructive example of the synthesis of this structural subclass of IMiDs (Scheme 3). 15 An optimized synthesis of the L-isoglutamine-derived building block 25 was necessary due to its limited commercial availability and the variable purity of commercial samples the team analyzed.…”

Section: Glutarimide Ring Constructionmentioning

confidence: 99%

Tactics and Strategies for the Synthesis of Cereblon Ligands

Villemure,

Nilewski,

Wang

et al. 2024

Synthesis

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Targeted protein degradation (TPD) has emerged as an important strategy to target disease-relevant proteins that were previously considered difficult to drug or even undruggable. Cereblon (CRBN) plays an outsized role in TPD as a preferred degradation-inducing effector protein for several reasons, including its anticipated broad protein substrate scope and its ligandability with drug-like small molecules. Notably, CRBN-based molecular glue degraders (MGDs) and proteolysis targeting chimeras (PROTACs) have shown success in clinical trials and, in some cases, as approved drugs. Thus, the interest in CRBN ligands within the pharmaceutical industry and academia has increased dramatically in recent years, highlighting the need for robust synthetic approaches towards them. This short review summarizes tactics and strategies to synthesize CRBN ligands, including the most recent developments in the field. Particular emphasis is put on the construction and direct functionalization of key CRBN binding motifs such as glutarimides and dihydrouracils.1 Introduction2 Cereblon Ligands with Glutarimide Binding Motif3 Cereblon Ligands with Dihydrouracil Binding Motif4 Cereblon Ligands with Other Binding Motifs5 Conclusions and Outlook

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Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation

Cited by 16 publications

References 19 publications

Engineering CRBN for rapid identification of next generation binders

Engineering CRBN for rapid identification of next generation binders

Simplifying Access to Targeted Protein Degraders via Nickel Electrocatalytic Cross‐Coupling

Tactics and Strategies for the Synthesis of Cereblon Ligands

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