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Rapid-kinetics degron benchmarking reveals off-target activities and mixed agonism-antagonism of MYB inhibitors

Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development of transcriptional inhibitors is hampered by the lack of a generally accepted functional cellular readout to characterize their target specificity and on-t...

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Detalles Bibliográficos
Autores principales: Harada, Taku, Perez, Monika W., Kalfon, Jérémie, Braes, Flora Dievenich, Batley, Rashad, Eagle, Kenneth, Nabet, Behnam, Leifer, Becky, Kruell, Jasmin, Paralkar, Vikram R., Stegmaier, Kimberly, Koehler, Angela N., Orkin, Stuart H., Pimkin, Maxim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10104119/
https://www.ncbi.nlm.nih.gov/pubmed/37066194
http://dx.doi.org/10.1101/2023.04.07.536032
Descripción
Sumario:Attenuating aberrant transcriptional circuits holds great promise for the treatment of numerous diseases, including cancer. However, development of transcriptional inhibitors is hampered by the lack of a generally accepted functional cellular readout to characterize their target specificity and on-target activity. We benchmarked the direct gene-regulatory signatures of six agents reported as inhibitors of the oncogenic transcription factor MYB against targeted MYB degradation in a nascent transcriptomics assay. The inhibitors demonstrated partial specificity for MYB target genes but displayed significant off-target activity. Unexpectedly, the inhibitors displayed bimodal on-target effects, acting as mixed agonists-antagonists. Our data uncover unforeseen agonist effects of small molecules originally developed as TF inhibitors and argue that rapid-kinetics benchmarking against degron models should be used for functional characterization of transcriptional modulators.