Host: Suze Farrell

Venue: MSI Small Lecture Theatre, SLS

This seminar is fully funded by external sources

Abstract:

The current TB drug pipeline is populated with small molecule drug candidates that act through inhibition of a number of specific protein-based targets. However, the inhibitor-focused drug development approach suffers from several drawbacks, including difficulty in identification of targets amenable to small-molecule disruption, locating druggable sites that adversely impact target activity, and balancing inhibitor potency with potential selectivity and toxicity concerns to establish a therapeutic window. This talk will describe the work of GCADDA4TB, a flagship programme for tuberculosis drug development established as part of the GC ADDA initiative, which is addressing these challenges by pivoting to the development of bacterial proteolysis targeting chimeras (BacPROTACs) as new antituberculosis agents. More specifically, the talk will describe the workflow by which BacPROTACs that target high value proteins of interest (POIs) are developed in a manner that capitalises on our teams’ experience and fulfil various vulnerability and target-assessment criteria. Our most recent successes – and our plans for future studies – will be highlighted to showcase that targeted protein degradation is a viable strategy for anti-tuberculosis drug development.

Bio:

Prof. Erick Strauss is regarded as a leading authority on the biosynthesis and enzymology of the essential metabolic cofactor coenzyme A (CoA) across organisms, and applying this knowledge to the development of novel antimicrobials for the treatment of infectious diseases. He currently leads the GC ADDA4TB consortium, a flagship project of the Grand Challenges Africa Drug Discovery Accelerator initiative funded by the Gates Foundation and LifeArc, with the expressed goal of exploring the development of a new antituberculosis agent through the implementation of a targeted protein degradation approach.

Erick is currently professor of Biochemistry at Stellenbosch University in South Africa. He obtained his PhD in Chemistry and Chemical Biology from Cornell University in the USA in 2003, with a focus on mechanistic enzymology. More than 50 postgraduate students and postdoctoral fellows have completed their training under his supervision, with some having established their own academic groups or found positions in industry, including in drug development.

His awards and honours include teaching awards from Cornell and Stellenbosch Universities; the President’s Award from the South African National Research Foundation (2008); the Beckman-Coulter Silver Medal from the South African Society for Biochemistry and Molecular Biology (2010); and the Raikes Medal from the South African Chemical Institute (2013). He is currently editorial advisory board member of the journals ACS Infectious Diseases and Biochemistry.

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Top in the UK for Research Quality in Biological and Biomedical Sciences

Venue: CeTPD Seminar Room

Abstract:

As drug discovery scientists look for more effective therapeutic strategies to treat disease, dual targeting inhibitors and PROTAC molecules are emerging as powerful agents that can overcome limitations of conventional single target agents. These classes of bifunctional molecules also carry new challenges for chemists and pharmacologists as they typically stray beyond conventional SAR and the historic “rules” for compound development.

In this presentation, case studies in an anti-cancer drug discovery (Dual inhibitors of BET/PI3K) and anti-viral drug discovery (MPro PROTACs for SARS CoV-2) from our group will be used to highlight successful and not-so-successful examples of bifunctional compound development.

References:

Pan, B.; Mountford, S. J.; Kiso, M.; Anderson, D. E.; Papadakis, G.; Jarman, K. E.; Tilmanis, D. R.; Maher, B.; Tran, T.; Shortt, J.; Yamayoshi, S.; Kawaoka, Y.; Thompson, P. E.; Greenall, S. A.; Warner, N. Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus. Commun Med (Lond) 2025, 5, 140.

Oh, D. H.; Ma, X.; Hogg, S. J.; He, J.; Kearney, C.; Brasacchio, D.; Susanto, O.; Maher, B.; Jennings, I. G.; Newbold, A.; Fraser, P.; Gruber, E.; Kats, L. M.; Gregory, G. P.; Johnstone, R. W.; Thompson, P. E.; Shortt, J. Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma. Proc Natl Acad Sci U S A 2023, 120, e2306414120.