MST and TRIC Technology to Reliably Study PROTAC Binary and Ternary Binding in Drug Development

Bartoschik, Tanja; Zoephel, Andreas; Rumpel, Klaus; Ciulli, A.; Heffern, Charles T.R.

doi:10.1007/978-1-0716-1665-9_6

Cited by 8 publications

(2 citation statements)

References 37 publications

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“…As well as those outlined above, additional techniques have been used to study binary and ternary complex formation. These include dynamic scanning calorimetry, [43,53] size-exclusion chromatography [16,23,54] microscale thermophoresis (MST), [55] native mass spectrometry, [56][57][58] and nuclear magnetic resonance (NMR). [51,59] These techniques serve as orthogonal assays to the main strategies such as TR-FRET and SPR, but they can also provide additional advantages.…”

Section: Other Techniques To Study Binary and Ternary Complex Formationmentioning

confidence: 99%

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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Section: Other Techniques To Study Binary and Ternary Complex Formationmentioning

confidence: 99%

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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“…Recently, an MST assay has been developed to investigate further this interaction due to its high sensitivity and the fact that it can be used in complex environment such as ternary complexes. In this case, a Kd value of 325 nM was calculated [ 56 ]. The agreement between the two technologies was excellent.…”

Section: Case Studiesmentioning

confidence: 99%

Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

Magnez

Bailly

Thuru

2022

IJMS

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The review highlights how protein–protein interactions (PPIs) have determining roles in most life processes and how interactions between protein partners are involved in various human diseases. The study of PPIs and binding interactions as well as their understanding, quantification and pharmacological regulation are crucial for therapeutic purposes. Diverse computational and analytical methods, combined with high-throughput screening (HTS), have been extensively used to characterize multiple types of PPIs, but these procedures are generally laborious, long and expensive. Rapid, robust and efficient alternative methods are proposed, including the use of Microscale Thermophoresis (MST), which has emerged as the technology of choice in drug discovery programs in recent years. This review summarizes selected case studies pertaining to the use of MST to detect therapeutically pertinent proteins and highlights the biological importance of binding interactions, implicated in various human diseases. The benefits and limitations of MST to study PPIs and to identify regulators are discussed.

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A Structural and Biophysical Perspective of Degrader Activity Through Ternary Complex Formation

Gadd

Aublette

2022

Inducing Targeted Protein Degradation

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MST and TRIC Technology to Reliably Study PROTAC Binary and Ternary Binding in Drug Development

Cited by 8 publications

References 37 publications

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

A Structural and Biophysical Perspective of Degrader Activity Through Ternary Complex Formation

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