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ProxiCapture reveals context-dependent CRBN interactome landscape of molecular glue degraders

ABSTRACT: Molecular glue degraders represent a rapidly expanding class of small molecules that reprogram E3 ubiquitin ligases to ubiquitinate and degrade disease-relevant proteins. Despite their therapeutic potential, the rational design of molecular glues remains challenging, underscoring the need for unbiased discovery strategies to identify new chemical targets. To address this challenge, we developed ProxiCapture, an affinity-based proteomics workflow that models the systemic behavior of molecular glues (MGs) by combining purified CRBN-ΔHBD protein with native cell or tissue lysates. ProxiCapture enables proteome-wide identification of degrader-dependent CRBN-protein interaction across diverse biological contexts.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Liver, Lymphoblast

DISEASE(S): Acute Leukemia,Liver Cancer

SUBMITTER: Rubina Kazi

LAB HEAD: Prof. Ivan

PROVIDER: PXD070567 | Pride | 2026-02-03

REPOSITORIES: Pride

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			Action	DRS
	20250130_HF_LC2_MAA_RK_12265_01_01.raw	Raw
	20250130_HF_LC2_MAA_RK_12265_01_02.raw	Raw
	20250130_HF_LC2_MAA_RK_12265_01_03.raw	Raw
	20250130_HF_LC2_MAA_RK_12265_01_04.raw	Raw
	20250130_HF_LC2_MAA_RK_12265_01_05.raw	Raw

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ProxiCapture reveals context-dependent CRBN interactome landscape of molecular glue degraders

Project description:Molecular glue degraders represent a rapidly expanding class of small molecules that reprogram E3 ubiquitin ligases to ubiquitinate and degrade disease-relevant proteins. Despite their therapeutic potential, the rational design of molecular glues remains challenging, underscoring the need for unbiased discovery strategies to identify new chemical targets. To address this challenge, we developed ProxiCapture, an affinity-based proteomics workflow that models the systemic behavior of molecular glues (MGs) by combining purified CRBN-ΔHBD protein with native cell or tissue lysates. ProxiCapture enables proteome-wide identification of degrader-dependent CRBN-protein interaction across diverse biological contexts.

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Project description:Cereblon (CRBN) is a ubiquitin ligase widely harnessed for targeted protein degradation. We report the discovery of a molecular glue that drives CRBN homo-dimerization and subsequent fast, potent, and selective CRBN degradation by the ubiquitin proteasome system. The structure of the complex reveals a unique mechanism whereby two molecular glues assemble into a helix-like structure and drive ternary complex formation by mimicking a protein degron in trans.

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Project description:Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing a privileged rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, molecular glues have predominantly been discovered by serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Using high-throughput chemical synthesis to diversify a ligand for the transcriptional coactivator ENL with 3,163 structurally diverse chemical building blocks, we discovered a compound dHTC1 that elicits potent, selective, and stereochemistry-dependent degradation of ENL by induced binding to CRL4CRBN. Unlike prior CRBN-based degraders, dHTC1 binds the ligase with high affinity only after forming the ENL:dHTC1 complex, relying on a hybrid interface of protein-protein and protein-ligand contacts. Altogether, this study points toward an expanded chemical space for co-opting the therapeutically important substrate receptor, CRBN, and a second proof-of-concept extending this approach to BRD4 further validates high-throughput chemistry as a facile tool to discover new degraders

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RNA polymerase III interactome

Project description:Many regulatory proteins and complexes have been identified which influence transcription by RNA polymerase (pol) II with a fine precision. In comparison, only a few regulatory proteins are known for pol III, which transcribes mostly house-keeping and non-coding RNAs. Yet, pol III transcription is precisely regulated under various stress conditions like starvation. We used proteomic approaches and pol III transcription complex components TFIIIC (Tfc6), pol III (Rpc128) and TFIIIB (Brf1) as baits to find identify the potential interactors through mass spectrometry-based proteomics. A large number of proteins were found in the interactome, which includes known chromatin modifiers, factors and regulators of transcription by pol I and pol II.

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Project description:Targeted protein degradation and induced proximity both refer to advanced strategies that leverage the recruitment of target proteins to another protein to facilitate their modification, regulation or degradation. As the biological complexity of molecular glues and degraders has become increasingly apparent, there is a growing need for advances in unbiased methodology to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue interactomes. We map the targets of 20 molecular glues across two orthogonal cell lines identifying 270 proteins as chemically recruited to CRBN and demonstrate the power of enrichment methods for identifying novel protein targets that are often overlooked using global whole cell screening methods. We not only drastically increase the breadth of zinc finger transcription factors that are targetable, but more importantly identify many novel non-zinc finger proteins as targets of IMiD molecular glues. We use alignments with structures obtained from the Alphafold2 database as a method to estimate confidence in experimental hits and we experimentally validate several targets to show direct interaction and subsequent ubiquitylation. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying new drug-induced protein interactions in cell lysates.

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