Oncotarget

Research Papers:

Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2

Leanne Milton-Harris, Mark Jeeves, Sarah A. Walker, Simon E. Ward and Erika J. Mancini _

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Oncotarget. 2020; 11:1737-1748. https://doi.org/10.18632/oncotarget.27580

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Abstract

Leanne Milton-Harris1, Mark Jeeves2, Sarah A. Walker3, Simon E. Ward4 and Erika J. Mancini1

1 School of Life Sciences, Biochemistry Department, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom

2 Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom

3 Sussex Drug Discovery Centre, University of Sussex, Brighton, BN1 9QJ, United Kingdom

4 Medicines Discovery Institute, Cardiff University, Park Place, Cardiff, CF10 3AT, United Kingdom

Correspondence to:

Erika J. Mancini,email: erika.mancini@sussex.ac.uk

Keywords: protein-protein interaction; leukaemia; T-ALL; drug discovery; LMO2

Received: December 24, 2019     Accepted: April 03, 2020     Published: May 12, 2020

ABSTRACT

Ectopic expression in T-cell precursors of LIM only protein 2 (LMO2), a key factor in hematopoietic development, has been linked to the onset of T-cell acute lymphoblastic leukaemia (T-ALL). In the T-ALL context, LMO2 drives oncogenic progression through binding to erythroid-specific transcription factor SCL/TAL1 and sequestration of E-protein transcription factors, normally required for T-cell differentiation. A key requirement for the formation of this oncogenic protein-protein interaction (PPI) is the conformational flexibility of LMO2. Here we identify a small molecule inhibitor of the SCL-LMO2 PPI, which hinders the interaction in vitro through direct binding to LMO2. Biophysical analysis demonstrates that this inhibitor acts through a mechanism of conformational modulation of LMO2. Importantly, this work has led to the identification of a small molecule inhibitor of the SCL-LMO2 PPI, which can provide a starting point for the development of new agents for the treatment of T-ALL. These results suggest that similar approaches, based on the modulation of protein conformation by small molecules, might be used for therapeutic targeting of other oncogenic PPIs.


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