Delineating the role of cooperativity in the design of potent PROTACs for BTK
| Autor: | Suman Luthra, Graham M. West, Jeremy T. Starr, Matthew Frank Brown, Matthew F. Calabrese, Jinshan Chen, Hongyao Zhu, Xiayang Qiu, Daniel P. Uccello, Matthew Merrill Hayward, Jeanne S. Chang, Jotham Wadsworth Coe, Kathleen A. Farley, Kris A. Borzilleri, Mark C. Noe, Justin I. Montgomery, Adam M. Gilbert, Veerabahu Shanmugasundaram, Lara C. Czabaniuk, Robert M. Oliver, Carmen N. Garcia-Irrizary, Brandon P. Schuff, Chuong Nguyen, Yingrong Xu, James Schiemer, Jaymin C. Shah, Xidong Feng, Mark Niosi, Jennifer A. Young, WeiDong Ding, Ayman El-Kattan, Adelajda Zorba, James F. Smith |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Cooperativity Ligands 03 medical and health sciences hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Bruton's tyrosine kinase Animals Polyubiquitin Cells Cultured Multidisciplinary biology Chemistry Cereblon Proteolysis targeting chimera Ubiquitination Protein-Tyrosine Kinases Ubiquitin ligase Cell biology Rats 030104 developmental biology Proteasome PNAS Plus Proteolysis biology.protein Thermodynamics Target protein Tyrosine kinase |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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