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Abstract. Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strate

TRI-611 induces the degradation of ALK fusion proteins via a previously undescribed CRBN recruitment motif, and its preclinical anti-tumour activity highlights TRI-611 as a potential new way of treati...

a, Schematic of TR-FRET screen used to identify molecular glues of CRBN and ALK. Europium-labelled streptavidin binds to biotinylated ALK and Ulight-labelled anti-His antibody binds to CRBN. When ALK and CRBN are brought into proximity in a ternary complex by a molecular glue, a TR-FRET signal is generated. b, Scatter plot of TR-FRET screen and identification of compound 1 as an ALK:CRBN molecular glue hit. Data points represent individual compounds sorted on the x-axis by compound ID number. c, Key features of compound 1. Papp: apparent permeability coefficient; MDR1: multidrug resistance 1 (P-glycoprotein); A-B: apical-basolateral; efflux ratio: Papp (apical-basolateral)/Papp (basolateral-apical); CNS MPO: central nervous system multiparameter optimization score; MLM: mouse liver microsomes; HLM: human liver microsomes. d, Measurement of induced ALK:CRBN proximity measured by TR-FRET as a dose response of compound 1 in the presence and absence of 10 µM CC-885, a GSPT1 MGD that binds to CRBN but does not recruit ALK. Data from n = 2 replicate wells are plotted and experiment was conducted once. e, Measurement of ALK:compound 1:CRBN ternary complex formation by SPR with immobilized ALK kinase domain, fixed CRBN, and the indicated concentrations of compound 1. KD value represents the mean and SD of 6...

🔬 What if, instead of simply blocking disease-causing proteins, we ...

TRI-611 induces the degradation of ALK fusion proteins via a previously undescribed CRBN recruitment motif, and its preclinical anti-tumour activity highlights TRI-611 as a potential new way of treating ALK-positive non-small-cell lung cancer.

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TRI-611 induces the degradation of ALK fusion proteins via a previously undescribed CRBN recruitment motif, and its preclinical anti-tumour activity highlights TRI-611 as a potential new way of treati...

Targeted protein degradation has emerged as a promising drug modality, with potential applications across many immuno-inflammatory diseases. KT-474 is an orally bioavailable interleukin-1 receptor-associated kinase 4 (IRAK4) heterobifunctional degrader evaluated in clinical trials for atopic dermatitis and hidradenitis suppurativa. Here we present structural, biophysical, and computational characterization of an IRAK4:KT-474:CRBN/DDB1 complex. Cryo-EM structure of the complex reveals a unique and non-native protein-protein interaction (PPI) surface mediated by a network of polar and apolar contacts, including key hydrophobic engagements mediated by CRBN Phe150. This complex exhibits negative cooperativity, arising from an interplay between weakly favorable PPI and conformational flexibility of the degrader. Moreover, the structure provides insight into the selective degradation profile of KT-474. Our results offer important insights into the mechanism of action of KT-474 and highlight

Glutarimide-containing Cereblon (CRBN) ligands are critical motifs for PROTACs, molecular glue degraders and next-generation Cereblon E3 ligase modulatory drugs (CELMoDs), which represent promising therapeutic modalities in targeted protein degradation. However, the multistep synthetic routes required to access glutarimide scaffolds continue to present formidable challenges for medicinal chemists, limiting rapid structure–activity relationship (SAR) exploration and late-stage diversification. To streamline access to these privileged motifs, modular and efficient methodologies are still highly desirable. Here, we report a unified organocatalytic synthesis platform for the rapid assembly of diverse glutarimide derivatives from readily available nitrogen heterocycles. Employing a sequence of phosphine-catalysed C–N bond formation, metal-free Giese addition and acid-mediated cyclisation, this approach provides high selectivity, broad functional group tolerance and operational simplicity un

We hypothesize that many proteins found to be degraded through MGD derivatives are already CRBN-engaged through generic MGDs, such as pomalidomide, yet not sufficiently to drive degradation. Such latent proximity inducers are prime candidates for degraders, as evident from a number of studies on CRBN as well as other E3 ligases correlating cellular degradation with biochemical binding properties, reporting that an approximately two- to threefold increase in target binding to CRBN–MGDs suffices to convert CRBN–MGD-bound proteins into robustly degraded ones24,26. Hence, knowing which proteins latently interact with CRBN–MGD E3 ligase complexes, even if not yet degraded, will inform CRBN target discovery. To identify CRBN–MGD-bound proteins on a large scale requires overcoming the limitations of traditional biochemical approaches, allowing us to profile thousands of protein interactions. We chose a highly parallel protein complementation assay27, in which a methotrexate-resistant murine dihydrofolate reductase (DHFR) is split into two fragments (‘DH’ and ‘FR’), which are fused to bait and prey proteins. The binding between the proteins reconstitutes DHFR activity, allowing yeast growth to serve as a proxy for interaction (Fig. 1a and Methods)28. We set out to test whether DH–bait and FR–prey complementation can also be induced by MGDs (GluePCA29). We first chose CRL4CRBN...

The latent interactions of molecular glue degraders are identified proteome-wide.

The latent interactions of molecular glue degraders are identified proteome-wide.

Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins…