Proteomics

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Delineating the role of cooperativity in the design of potent PROTACs for BTK


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

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human) Rattus Rattus (black Rat)

TISSUE(S): Spleen, Lung, Cell Culture

SUBMITTER: chuong nguyen  

LAB HEAD: CHUONG NGUYEN

PROVIDER: PXD010606 | Pride | 2018-07-31

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
IB_evidence.txt Txt
IB_parameters.txt Txt
IB_peptides.txt Txt
IB_proteinGroups.txt Txt
NG_05262017_RAMOS_BTK_PF7014_PF7092_MS2REP1_01.raw Raw
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Publications

Delineating the role of cooperativity in the design of potent PROTACs for BTK.

Zorba Adelajda A   Nguyen Chuong C   Xu Yingrong Y   Starr Jeremy J   Borzilleri Kris K   Smith James J   Zhu Hongyao H   Farley Kathleen A KA   Ding WeiDong W   Schiemer James J   Feng Xidong X   Chang Jeanne S JS   Uccello Daniel P DP   Young Jennifer A JA   Garcia-Irrizary Carmen N CN   Czabaniuk Lara L   Schuff Brandon B   Oliver Robert R   Montgomery Justin J   Hayward Matthew M MM   Coe Jotham J   Chen Jinshan J   Niosi Mark M   Luthra Suman S   Shah Jaymin C JC   El-Kattan Ayman A   Qiu Xiayang X   West Graham M GM   Noe Mark C MC   Shanmugasundaram Veerabahu V   Gilbert Adam M AM   Brown Matthew F MF   Calabrese Matthew F MF  

Proceedings of the National Academy of Sciences of the United States of America 20180716 31


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 reg  ...[more]

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