George Burslem, Ph.D.
1004 Stellar-Chance Labs
422 Curie Blvd
Philadelphia, PA 19104-6059
The Burslem lab is interested in developing chemical tools to understand and modulate lysine post-translational modifications, specifically acetylation and ubiquitination. The laboratory is particularly interested in novel pharmacological approaches to modulate post-translational modifications which regulate gene expression and protein stability.
Contribution to Science
Targeted Protein Degradation
Over the last 20 years, the Crews lab has pioneered the concept of targeted protein degradation as a powerful approach to understand and modulated biological systems. By co-opting the ubiquitin proteasome system (UPS), heterobifunctional small molecules can induce the degradation of target proteins within a cellular context. Proteolysis Targeting Chimera (PROTACs) contain two distinct chemical recruiting elements tethered by a linker; one for an E3 ligase and one for the target protein. We were able to demonstrate that this approach is capable of inducing the degradation of transmembrane receptor tyrosine kinases despite the fact that they are not usually UPS substrates. This enable us to develop compounds with enhanced activity against FLT-3 ITD as a potential therapeutic for acute myeloid leukaemia. Additionally, PROTACs represent a useful tool for the study of protein function which we demonstrated, in collaboration with the Druker lab, enabled the study of kinase independent roles of BCR-Abl in chronic myeloid leukaemia stem cells.
- Burslem, G.M., and Crews, C.M. (2017). Small-Molecule Modulation of Protein Homeostasis. Chemical Reviews 117, 11269-11301.
- Burslem, G.M., Schultz, A.R., Bondeson, D.P., Eide, C.A., Savage Stevens, S.L., Druker, B.J., and Crews, C.M. (2019). Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-mediated Targeted Protein Degradation. Cancer Research, 79, 4744-4753
- Burslem, G.M., Smith, B.E., Lai, A.C., Jaime-Figueroa, S., McQuaid, D.C., Bondeson, D.P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018). The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chemical Biology 25, 67-77.
- Bondeson, D.P., Smith, B.E., Burslem, G.M., Buhimschi, A.D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B.D., Ishchenko, A., and Crews, C.M. (2018). Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. Cell Chemical Biology 25, 78-87.
- Burslem, G.M., Song, J., Chen, X., Hines, J., and Crews, C.M. (2018). Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion. Journal of the American Chemical Society 140, 16428-16432.
Inhibition of the HIF-1α/p300 Protein-Protein Interaction
The transcription factor, hypoxia inducible factor 1α (HIF-1 α), plays a central role in the cellular response to hypoxia. It does so by forming a complex with the transcriptional co-activator and epigenetic regulator, p300. Since solid tumours rapidly deplete their oxygen supply and become hypoxic, inhibition of the HIF‐1α–p300 interaction represents an attractive approach for their treatment. Using proteomimetic, phage display and bionic protein approaches, we were able to identify several inhibitors of this crucial protein-protein interaction, including the first biophysically characterized small molecule inhibitor.
- Burslem, G.M., Kyle, H.F., Nelson, A., Edwards, T.A., and Wilson, A.J. (2017). Hypoxia inducible factor (HIF) as a model for studying inhibition of protein-protein interactions. Chemical Science, 8, 4188-4202.
- Burslem, G.M., Kyle, H.F., Breeze, A.L., Edwards, T.A., Nelson, A., Warriner, S.L., and Wilson, A.J. (2014). Small-Molecule Proteomimetic Inhibitors of the HIF-1α–p300 Protein–Protein Interaction. ChemBioChem, 15, 1083-1087.
- Burslem, G.M., Kyle, H.F., Breeze, A.L., Edwards, T.A., Nelson, A., Warriner, S.L., and Wilson, A.J. (2016). Towards “bionic” proteins: replacement of continuous sequences from HIF-1α with proteomimetics to create functional p300 binding HIF-1α mimics. Chemical Communications, 52, 5421-5424.
- Kyle, H.F., Wickson, K.F., Stott, J., Burslem, G.M., Breeze, A.L., Tiede, C., Tomlinson, D.C., Warriner, S.L., Nelson, A., Wilson, A.J., et al. (2015). Exploration of the HIF-1α/p300 interface using peptide and Adhiron phage display technologies. Molecular BioSystems, 11, 2738-2749.
- Burslem, G.M., Kyle, H.F., Prabhakaran, P., Breeze, A.L., Edwards, T.A., Warriner, S.L., Nelson, A., and Wilson, A.J. (2016). Synthesis of highly functionalized oligobenzamide proteomimetic foldamers by late stage introduction of sensitive groups. Organic & Biomolecular Chemistry, 14, 3782-3786.
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