Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

Jarusiewicz, Jamie A.; Yoshimura, Satoshi; Mayasundari, Anand; Actis, Marisa; Aggarwal, Anup; McGowan, Kevin M.; Yang, Lei; Li, Yong; Fu, Xiang Dong; Mishra, Vibhor; Heath, Richard J.; Narina, Shilpa; Pruett-Miller, Shondra M.; Nishiguchi, Gisele; Yang, Jun J.; Rankovic, Zoran

doi:10.1021/acsmedchemlett.2c00436

Cited by 14 publications

(6 citation statements)

References 15 publications

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“…63,64 Phenyl dihydrouracil 27 was viewed as particularly attractive as it eliminates the racemization prone chiral center in the glutarimide motif of IMiD ligands, while maintaining CRBN binding affinity, and also exhibits greater chemical stability. 65,66 CRBN ligands 27 and 30 were synthesized following reported literature procedures (Scheme 3). 64,67 The dihydrouracil 27 was further derivatized with substituted piperidine (31) and spiropiperidine (32,33) motifs to introduce rigidity to the linker.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…In recent years, much effort has been dedicated to developing new CRBN recruiting ligands with the goal of optimizing binding affinity, improving stability, and abrogating the molecular glue off-target activity of Immunomodulatory Drug (IMiD)-based ligands such as lenalidomide. − With the optimal linker lengths now established, we investigated two recently reported alternative CRBN ligands 27 and 30 in this context. , Phenyl dihydrouracil 27 was viewed as particularly attractive as it eliminates the racemization prone chiral center in the glutarimide motif of IMiD ligands, while maintaining CRBN binding affinity, and also exhibits greater chemical stability. , …”

Section: Resultsmentioning

confidence: 99%

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PROTACs Targeting MLKL Protect Cells from Necroptosis

et al. 2023

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Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chemical means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamidebased MLKL ligand leading to the identification of a PROTAC molecule that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quantitative relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

PROTACs Targeting MLKL Protect Cells from Necroptosis

et al. 2023

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“…In this manuscript, we report the identification, synthesis, and characterization of a series of such nontraditional CRBN binders. While there have been several recent disclosures of similar nontraditional CRBN binders in the scientific − and patent literature, these had not been disclosed at the time of the work described here.…”

Section: Introductionmentioning

confidence: 99%

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

Norris,

Ba,

Rhodes

et al. 2023

J. Med. Chem.

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“…Recently, three groups reported on phenyl dihydrouracil derivatives (IV) as CRBN-engaging agents. [20][21][22] These ligands combined several desirable features, including improved resistance to hydrolytic degradation. Furthermore, replacing the C-3 carbon of the glutarimide ring with nitrogen addressed commonly challenged racemization issues of IMiD-based degraders.…”

Section: Introductionmentioning

confidence: 99%

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

Steinebach

Sosič

Bricelj

et al. 2023

Preprint

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Immunomodulatory imide drugs (IMiDs) such as thalidomide, pomalidomide, and lenalidomide represent the most typical cereblon (CRBN) recruiters that are frequently utilized in proteolysis-targeting chimera (PROTAC) design. These CRBN binders, however, cause degradation of IMiD neosubstrates and are innately unstable as they undergo hydrolytic degradation under mild conditions. Here we present the systematic approach towards novel non-phthalimide CRBN binders that were obtained via the simultaneous optimization of their physiochemical properties, stability, on-target affinity, and off-target neosubstrate modulation features. Our efforts led to the discovery of conformationally-locked benzamide-type derivatives that mimic the interactions of the natural CRBN degron, displayed improved chemical stability, and showed a favorable selectivity profile with respect to the recruitment of neosubstrates. The usefulness of the most potent ligands was demonstrated by their conversion into potent degraders of BRD4 and HDAC6 that displayed superiority compared to previously described benchmark PROTACs. We show that our diversified CRBN ligands offer opportunities to design chemically inert proximity-inducing compounds with reduced neomorphic E3 ligase activity of CRBN.

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Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design

Cited by 14 publications

References 15 publications

PROTACs Targeting MLKL Protect Cells from Necroptosis

PROTACs Targeting MLKL Protect Cells from Necroptosis

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

Leveraging Ligand Affinity and Properties: Discovery of Novel Benzamide-Type Cereblon Binders for the Design of PROTACs

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