Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function

Luo, Mai; Spradlin, Jessica N.; Boike, Lydia; Tong, Bingqi; Brittain, Scott M.; McKenna, Jeffrey M.; Tallarico, John A.; Schirle, Markus; Maimone, Thomas J.; Nomura, Daniel K.

doi:10.1016/j.chembiol.2021.01.005

Cited by 100 publications

(110 citation statements)

References 30 publications

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“…A small molecule, that accessed the same cysteine targeted by nimbolide was incorporated into a BRD4-targeting PROTAC ( Luo et al, 2021 ). Starting material 296 was first protected with a tetrahydropyranyl ether to form 297 and then reacted with 4-bromoacetophenone.…”

Section: E3 Ligasesmentioning

confidence: 99%

“…Following a deprotection, 298 was obtained and the OH alkylated with a bromo linker, yielding 299 . Finally, compound 300 can be achieved over 2 steps ( Scheme 52 ) ( Luo et al, 2021 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

“…pyridinium p -toluenesulfonate, MeOH, 55°C, 3 h, 72% yield; c) linker-Br, K 2 CO 3 , DMF, 60°C, 5 h, 87% yield for linker used; d) i. Hydrazine monohydrate, EtOH, 80°C, 5 h; ii. chloroacetyl chloride, Et 3 N, CH 2 Cl 2 , 0°C, 30 min, then rt, overnight, 58% yield ( Luo et al, 2021 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

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E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

et al. 2021

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Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

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Section: E3 Ligasesmentioning

confidence: 99%

“…Following a deprotection, 298 was obtained and the OH alkylated with a bromo linker, yielding 299 . Finally, compound 300 can be achieved over 2 steps ( Scheme 52 ) ( Luo et al, 2021 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

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E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

et al. 2021

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“…Subsequently, Tong, Spradlin et al expanded the utility of nimbolide-based PROTACs demonstrating selective BCR-ABL degradation when linked onto the kinase inhibitor dasatinib 6 . Luo and Spradlin et al then performed a target-based ABPP screen against RNF114 to discover a fully synthetic covalent RNF114 recruiter EN219 that successfully mimics nimbolide action as an RNF114 recruiter for TPD applications wherein the authors demonstrated RNF114-dependent degradation of BRD4 and BCR-ABL by linking EN219 onto JQ1 or dasatinib, respectively 7 . In a third successful example, Zhang et al incorporated covalent scout fragments into PROTACs to screen for FKBP12 degradation.…”

Section: Main Textmentioning

confidence: 99%

Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

et al. 2021

Preprint

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Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number of E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress. By targeting Cys186 in FEM1B, EN106 disrupts recognition of the key reductive stress substrate of FEM1B, FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications, in which we demonstrate that a PROTAC linking EN106 to the BET Bromodomain inhibitor JQ1 leads to specific FEM1B- and proteasome-dependent degradation of BRD4 in cells. Our study showcases a covalent ligand that targets a natural E3 ligase-substrate binding site and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters that can be deployed for TPD applications.

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“…A typical PROTAC consists of three parts: a POI binding ligand, an E3 ubiquitin-binding ligand, and a linker connecting two ligands. Despite the presence of >600 putative E3 ligases in the human proteome, only a handful of E3 ligase ligands (CRBN [ 31 , 32 ], VHL [ 33 , 34 , 35 ], MDM [ 36 , 37 , 38 ], IAP [ 39 ], RNF114 [ 40 , 41 ], DCAF15 [ 42 ], DCAF 16 [ 43 ], and FEM1B [ 44 ]) are readily available for the design of a PROTAC ( Figure 4 ). The PROTAC approach has been successfully applied to degrade kinases, G protein-coupled receptors, nuclear receptors, membrane proteins, transcription factors, and neurodegenerative proteins aggregates [ 23 , 26 , 27 , 28 , 29 , 30 , 36 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase

Rana

Mallareddy

Singh

et al. 2021

Cancers

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The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule–protein interactions. On the other hand, Molecular glues function by converting the target protein into a “neo-substrate” for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.

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Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function

Cited by 100 publications

References 30 publications

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

Discovery of a Covalent FEM1B Recruiter for Targeted Protein Degradation Applications

Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase

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