Advances in Cereblon-Targeted Cancer Therapies

From IMiDs to CELMoDs – The Evolution of Targeted Protein Degradation 🧬 For years, Lenalidomide and Pomalidomide (IMiDs) have been the backbone of treatment for Multiple Myeloma. While their discovery was a landmark in hematology, our understanding of how they work—by hijacking the Cereblon (CRBN) E3 ligase to degrade Ikaros and Aiolos—has opened the door to a new, more potent era: the CELMoDs. 🧬 The "Molecular Glue" Upgrade Unlike traditional IMiDs, Cereblon E3 Ligase Modulators (CELMoDs) are not just next-generation analogues. They are rationally engineered "molecular glues" designed for: Higher Potency: Stronger binding affinity to Cereblon. Faster Degradation: More efficient "search-and-destroy" kinetics for target proteins. Overcoming Resistance: Effectiveness even in patients who no longer respond to Lenalidomide. 🔬 Spotlight on the Pipeline: Mezigdomide (CC-92480): Specifically designed for maximal protein degradation. It’s showing remarkable results in Relapsed/Refractory Multiple Myeloma, proving that we can still hit the target when traditional therapies fail. Iberdomide (CC-220): With a very high affinity for CRBN, it is being explored not only in Myeloma but also in Systemic Lupus Erythematosus (SLE), showing how "reprogramming" the immune system can treat autoimmune diseases. Golcadomide (CC-99282): A precision tool for B-cell malignancies (like DLBCL). It demonstrates how we can fine-tune the chemical scaffold to target specific lymphoma subtypes with higher selectivity. 🧪 The Bottom Line We are moving from the serendipitous discovery of IMiDs to the surgical precision of CELMoDs. For organic and medicinal chemists, this is a masterclass in how understanding degradation kinetics can lead to life-changing drugs. I would like to hear from the MedChem specialists on how this changes on the molecular structure impacted the biological effect? Let’s discuss below! 👇 #MedicinalChemistry #Oncology #DrugDiscovery #BMS #MultipleMyeloma #CELMoDs #ProteinDegradation #PharmaInnovation

A recent Nature paper from Harvard University and GSK reports the discovery of a previously unrecognized allosteric binding site on cereblon (CRBN), separate from the canonical thalidomide-binding domain. The authors identify a cryptic, evolutionarily conserved pocket in the helical bundle domain that binds the small molecule SB-405483. Binding at this site does not compete with orthosteric ligands. Instead, it shifts CRBN between different shapes, which in turn changes how neosubstrates are recruited. Structural data show that allosteric binding biases CRBN toward closed and intermediate conformations (including the previously unobserved CRBNint state), offering a mechanistic explanation for the altered degradation profiles. Taken together, the work introduces allosteric modulation as a mechanistically grounded way to steer degradation outcomes. Although the allosteric ligand itself is best viewed as a tool compound, the underlying principle points to a new way to tune selectivity and potentially reduce known CRBN liabilities. #molecularglue #targetedproteindegradation #drugdiscovery #crbn

𝗘𝘅𝗽𝗮𝗻𝗱𝗶𝗻𝗴 𝘁𝗵𝗲 𝗙𝗿𝗼𝗻𝘁𝗶𝗲𝗿 𝗼𝗳 𝗧𝗮𝗿𝗴𝗲𝘁𝗲𝗱 𝗣𝗿𝗼𝘁𝗲𝗶𝗻 𝗗𝗲𝗴𝗿𝗮𝗱𝗮𝘁𝗶𝗼𝗻 𝘄𝗶𝘁𝗵 𝗛𝗶𝗴𝗵‑𝗧𝗵𝗿𝗼𝘂𝗴𝗵𝗽𝘂𝘁 𝗣𝗿𝗼𝘁𝗲𝗼𝗺𝗶𝗰𝘀 A new Nature Communications study delivers a proteomics‑first discovery engine for molecular glue degraders, mapping the cereblon (CRBN) neosubstrate landscape with unprecedented breadth. Using Bruker timsTOFs and diaPASEF (and slicePASEF for ubiquitinomics), the NEOsphere Biotechnologies GmbH team ran 720 samples and quantified ~10K with (median CV ~6%). This enabled unbiased screening of 100 CRBN ligands and validation of 50 previously unreported neosubstrates, including KDM4B, G3BP2, and VCL. The future of precision medicine isn’t just inhibiting proteins, it’s removing them. With platforms like this, the “undruggable” keeps shrinking. #StayCurious and congrats to Martin Steger Henrik Daub Zoran Rankovic and the rest of the team! https://lnkd.in/gFDrdbMV #Proteomics #timsTOF #diaPASEF #TargetedProteinDegradation #MolecularGlues #DIA #Ubiquitinomics #DrugDiscovery #PrecisionMedicine

Expanding the drugable genome with targeted glue degraders: Molecular glue degraders (MGDs) offer a novel approach for targeting proteins previously been considered as un-drugable by traditional small molecules. They redirect E3 ubiquitin ligases to tag new protein targets for degradation. Although there has been progress, MGD discovery mostly relies on empirical screening, particularly for proteins with a β-hairpin motif recognized by the cereblon (CRBN) substrate receptor in the presence of an MGD. A recent Science paper presents a clever method for identifying and validating degrons beyond the standard β-hairpin. The authors used computational mining (against PDB and AlphaFold2 models) along with experimental screening and validation to systematically expand the known CRBN neosubstrate range. This epitope-centric screening approach increases the number of identified neosubstrates suitable for targeted protein degradation and may be used to expand the application targeted protein degradation towards previously “un-drugable” targets. Some of these newly discovered targets (e.g. Vav1) have therapeutic potential. In summary, this technology holds great potential for the generation of more specific MGDs for future clinical use of targeted protein degradation. Publication: https://lnkd.in/eNBM6k4e Further reading: https://lnkd.in/ezWu8mM2 https://lnkd.in/eNVVt3Jg https://lnkd.in/ed7z5eVi https://lnkd.in/eNVVt3Jg https://lnkd.in/eRHUb9WR