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Angus Cowan – University of Dundee

01/03/2024 11:00 am - 01/03/2024 12:00 pm
Location
Davis Auditorium

WEHI Special Structural Biology Seminar hosted by Professor Peter Czabotar
 

Angus Cowan
Senior Drug Discovery Scientist, School of Life Sciences, University of Dundee, Scotland
 

Targeted protein degradation via intramolecular bivalent glues

 

Davis Auditorium

Join via TEAMS

Including Q&A session

 

Angus obtained his PhD in 2017 at WEHI (Melbourne) under the supervision of Professors Peter Czabotar and Peter Colman, investigating the structure and function of pro-apoptotic BCL-2 family proteins. After a short postdoc under Professor Czabotar working as part of a team collaborating with an industry partner to develop modulators of necroptosis, he joined the group of Professor Alessio Ciulli at the University of Dundee in January 2020. Supported by a Marie Skłodowska-Curie Fellowship, Angus’ research focused on structural and functional investigation of substrate receptors of CRL4 E3 ligases, with a view to exploiting them for targeted protein degradation with PROTACs and molecular glues. His work on structural and biophysical characterisation of DCAF11- and DCAF16-recruiting degrader molecules was part of a collaborative effort that uncovered a novel modality in targeted protein degradation termed intramolecular bivalent glues. In October 2023 he took up the role of Senior Drug Discovery Scientist at the Centre for Targeted Protein Degradation (University of Dundee) collaborating with Boehringer Ingelheim to develop novel PROTACs.

 

Targeted protein degradation is a pharmacological modality based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via bifunctional compounds (PROTACs) composed of two separate warheads that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target. Using orthogonal genetic screening, biophysical characterization, and structural reconstitution, we investigated the mechanism of action of bifunctional BRD2/4 degraders (IBG1-4) and found that – instead of connecting target and ligase in trans as PROTACs do – they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change glues BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target-ligase affinities which do not translate to BRD4 degradation in absence of compound. Structural insights into the ternary BRD4:IBG1:DCAF16 complex guided the rational design of improved degraders of low picomolar potency. We thus introduce a new modality in targeted protein degradation, termed intramolecular bivalent glues (IBGs), which work by bridging protein domains in cis to enhance surface complementarity with E3 ligases for productive ubiquitination and degradation.

 

All welcome!

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