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Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay

21 June 2021, Version 1
Working Paper
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Cooperativity is an important parameter to understand the ternary complexes formed by protein degraders. We developed fluorine NMR competition binding experiments to determine cooperativity of PROTACs. We show applicability to estimate both positive and negative cooperativity, also with homo-dimerizers, and highlight key features and considerations for optimal assay development.

Keywords

PROTAC
proteolysis-targeting chimera
cooperativity
ternary complex
NMR spectroscopy
19F NMR
VHL
displacement assay

Supplementary materials

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Supporting Information
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Supporting Information: Electronic Supplementary Information (ESI) available: Methods, details of data fitting and additional plots.
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Now Published

Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay [opens in a new tab]
Guilherme Vieira de Castro, Alessio Ciulli journal article
RSC Medicinal Chemistry , Volume 12, Issue 10
Online publication date: 2021

Version History

Jun 21, 2021 Version 1

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The content is available under CC BY 4.0 [opens in a new tab]

DOI

10.26434/chemrxiv-2021-zj19k
D O I: 10.26434/chemrxiv-2021-zj19k [opens in a new tab]

Funding

European Research Council
ERC-2012-StG-311460 DrugE3CRLs to A.C.
CAPES
PhD Studentship 7148-14-3 to G. V. C.
Wellcome Trust
100476/Z/12/Z
Wellcome Trust
094090/Z/10/Z

Author’s competing interest statement

The Ciulli laboratory receives or has received sponsored research support from Almirall, Amphista Therapeutics, Boehringer Ingelheim, Eisai, Nurix Therapeutics, and Ono Pharmaceutical. A.C. is a scientific founder, shareholder, and consultant of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms.

Ethics

The author(s) declare that they have sought and gained approval from the relevant ethics committee/IRB for this research and its publication.

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