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

Guilherme Vieira de Castro; Alessio Ciulli

doi:10.1039/d1md00215e

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

Guilherme Vieira de Castro, Alessio Ciulli (Lead / Corresponding author)

Biological Chemistry and Drug Discovery

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

117 Downloads (Pure)

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.

Original language	English
Pages (from-to)	1765-1770
Number of pages	6
Journal	RSC Medicinal Chemistry
Volume	12
Early online date	24 Aug 2021
DOIs	https://doi.org/10.1039/d1md00215e
Publication status	Published - Oct 2021

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Pharmaceutical Science
Drug Discovery
Organic Chemistry

Access to Document

10.1039/d1md00215e

Author Accepted ManuscriptAccepted author manuscript, 0.99 MB

3 Finished

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research
A Translational Engine for Biomedical Discoveries (Strategic Grant)
Fairlamb, A. (Investigator) & Gilbert, I. (Investigator)
1/01/13 → 30/09/15
Project: Research
State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B. (Investigator), Lilley, D. (Investigator), Owen-Hughes, T. (Investigator), Wyatt, P. (Investigator) & van Aalten, D. (Investigator)
1/03/12 → 28/02/17
Project: Research

11 Citations
1 Comment/debate

Erratum: Estimating the cooperativity of PROTAC-induced ternary complexes using ¹⁹F NMR displacement assay (RSC Med. Chem. (2021) 12 (1765-1770) DOI: 10.1039/D1MD00215E)
de Castro, G. V. & Ciulli, A., Jan 2022, In: RSC Medicinal Chemistry. 13, 1, p. 98 1 p.
Research output: Contribution to journal › Comment/debate › peer-review

Open Access
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2 Citations (Scopus)

79 Downloads (Pure)

Cite this

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title = "Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay",

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.",

author = "{de Castro}, {Guilherme Vieira} and Alessio Ciulli",

note = "This project has received funding from the European Research Council (ERC) under the European Union's Seventh Frame-work Programme (FP7/2007–2013) as a Starting Grant to A. C. (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs) and the Coordena{\c c}{\~a}o de Aperfei{\c c}oamento de Pessoal de N{\'i}vel Superior (CAPES, PhD Studentship 7148-14-3 to G. V. C.). Biophysics and drug discovery activities were supported by Wellcome Trust strategic awards to Dundee (100476/Z/12/Z and 094090/Z/10/Z, respectively). We thank Michael Zengerle, Andrea Testa, Chiara Maniaci and Miriam Girardini for the synthesis of the PROTACs used in this study and Scott Hughes for helpful discussions.",

year = "2021",

month = oct,

doi = "10.1039/d1md00215e",

language = "English",

volume = "12",

pages = "1765--1770",

journal = "RSC Medicinal Chemistry",

issn = "2632-8682",

publisher = "Royal Society of Chemistry",

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T1 - Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay

AU - de Castro, Guilherme Vieira

AU - Ciulli, Alessio

N1 - This project has received funding from the European Research Council (ERC) under the European Union's Seventh Frame-work Programme (FP7/2007–2013) as a Starting Grant to A. C. (grant agreement no. ERC-2012-StG-311460 DrugE3CRLs) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, PhD Studentship 7148-14-3 to G. V. C.). Biophysics and drug discovery activities were supported by Wellcome Trust strategic awards to Dundee (100476/Z/12/Z and 094090/Z/10/Z, respectively). We thank Michael Zengerle, Andrea Testa, Chiara Maniaci and Miriam Girardini for the synthesis of the PROTACs used in this study and Scott Hughes for helpful discussions.

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

U2 - 10.1039/d1md00215e

DO - 10.1039/d1md00215e

M3 - Article

C2 - 34778777

AN - SCOPUS:85117759958

SN - 2632-8682

VL - 12

SP - 1765

EP - 1770

JO - RSC Medicinal Chemistry

JF - RSC Medicinal Chemistry

ER -

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

Abstract

ASJC Scopus subject areas

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Projects

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)

A Translational Engine for Biomedical Discoveries (Strategic Grant)

State-of-the-Art Facilities for Structural Biology at the University of Dundee

Research output

Erratum: Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay (RSC Med. Chem. (2021) 12 (1765-1770) DOI: 10.1039/D1MD00215E)

Cite this

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

Erratum: Estimating the cooperativity of PROTAC-induced ternary complexes using ¹⁹F NMR displacement assay (RSC Med. Chem. (2021) 12 (1765-1770) DOI: 10.1039/D1MD00215E)