A molecular glue degrader of the WIZ transcription factor for fetal hemoglobin induction
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Erythrocyte
DISEASE(S): Sickle Cell Anemia
SUBMITTER: 
Amanda Hachey
LAB HEAD: Amanda Hachey
PROVIDER: PXD046433 | Pride | 2024-07-08
REPOSITORIES: Pride
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Project description:Stimulator of interferon genes (STING) is a central component of the pathway sensing the presence of cytosolic nucleic acids, having a key role in type I interferon innate immune response. Localized at the endoplasmic reticulum (ER), STING becomes activated by cGAMP, which is generated by the intracellular DNA sensor cyclic GMP-AMP synthase (cGAS). Due to its critical role in physiological function and its’ involvement in a variety of diseases, STING has been a notable focus for drug discovery. Recent advances in drug discovery allow the targeting of proteins previously considered “un-druggable” by novel mechanism of actions. Molecular glue degraders are defined as the compounds leading targeted protein degradation (TPD) by creating novel ligase-substrate interactions. Here, we identified AK59 as a novel molecular glue degrader for STING. A genome-wide, CRISPR/Cas9 knockout screen showed that the compound-mediated degradation of STING by AK59 is compromised by the loss of HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4), ubiquitin-like modifier activating enzyme 5 (UBA5) and ubiquitin like modifier activating enzyme 6 (UBA6). While UBA5 and UBA6 could be the auxiliary factors for AK59 activity, our results indicate that HERC4 is the main E3 ligase for the observed degradation mechanism. Validation by individual CRISPR knockouts, co-immunoprecipitations, as well as proximity mediated reporter assays suggested that AK59 functions as a glue degrader by forming a novel interaction between STING and HERC4. Furthermore, our data reveals that AK59 was effective on the most common pathological STING mutations that cause STING-associated vasculopathy with onset in infancy (SAVI), suggesting a potential clinical application of this mechanism. Thus, these findings not only reveal a novel mechanism for compound-induced degradation of STING but also utilize HERC4 as potential E3 ligase that for TPD, enabling novel therapeutic applications.
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Project description:Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. To investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical, and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design.
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