Delineating the role of cooperativity in the design of potent PROTACs for BTK
Adelajda Zorba,Chuong Nguyen,Yingrong Xu,Jeremy T. Starr,Kris A. Borzilleri,James F. Smith,Hongyao Zhu,Kathleen A. Farley,WeiDong Ding,James Schiemer,Xidong Feng,Jeanne S. Chang,Daniel P. Uccello,Jennifer A. Young,Carmen N. Garcia-Irrizary,Lara C. Czabaniuk,Brandon P. Schuff,Robert M. Oliver,Justin I. Montgomery,Matthew Merrill Hayward,Jotham Wadsworth Coe,Jinshan Chen,Mark Niosi,Suman Luthra,Jaymin C. Shah,Ayman El-Kattan,Xiayang Qiu,Graham M. West,Mark C. Noe,Veerabahu Shanmugasundaram,Adam M. Gilbert,Matthew Frank Brown,Matthew F. Calabrese +32 more
TLDR
It is shown that within a Bruton’s tyrosine kinase/cereblon PROTAC system, potent knockdown correlates with alleviation of steric clashes in the absence of thermodynamic cooperativity, which broadens the scope of PROTAC applications and affects fundamental design criteria across the field.Abstract:
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously “undruggable” targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK–CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.read more
Citations
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PROTAC targeted protein degraders: the past is prologue
TL;DR: Targeted protein degradation with proteolysis-targeting chimeras (PROTACs) has the potential to tackle disease-causing proteins that have historically been highly challenging to target with conventional small molecules as mentioned in this paper .
Journal ArticleDOI
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
George M. Burslem,Craig M. Crews +1 more
TL;DR: The burgeoning field of proteolysis-targeting chimeras (PROTACs), which are capable of modulating protein concentrations at a post-translational level by co-opting the ubiquitin-proteasome system, are described and their application to drug discovery is described.
Journal ArticleDOI
Targeted protein degradation: expanding the toolbox.
TL;DR: Opportunities and challenges for expanding the applicability of targeted protein degradation are discussed, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.
Journal ArticleDOI
PROteolysis TArgeting Chimeras (PROTACs) - Past, Present and Future
TL;DR: Important milestones in the development of the PROTAC technology are addressed, as well as key findings from this previous year are emphasized and future directions of this promising drug discovery modality are highlighted.
Journal ArticleDOI
PROTACs: great opportunities for academia and industry.
TL;DR: Although PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic.
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TL;DR: Using quantitative proteomics, it is found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKzF3, by the CRBN-CRL4 ubiquitin ligase, which are essential transcription factors in multiple myeloma.
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Daniel P. Bondeson,Alina Mares,Ian Edward David Smith,Ko Eunhwa,Sebastien Andre Campos,Afjal Hussain Miah,Katie E Mulholland,Natasha Routly,Dennis L. Buckley,Jeffrey L. Gustafson,Nico Zinn,Paola Grandi,Satoko Shimamura,Giovanna Bergamini,Maria Faelth-Savitski,Marcus Bantscheff,Carly S. Cox,Deborah A. Gordon,Ryan R. Willard,John J. Flanagan,Linda N. Casillas,Bartholomew J. Votta,Willem den Besten,Kristoffer Famm,Laurens Kruidenier,Paul S. Carter,John D. Harling,Ian Churcher,Craig M. Crews +28 more