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

Milton-Harris, Leanne, Jeeves, Mark, Walker, Sarah A., Ward, Simon E. ORCID: https://orcid.org/0000-0002-8745-8377 and Mancini, Erika J. 2020. Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2. Oncotarget 11 (19) , pp. 1737-1748. 10.18632/oncotarget.27580

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Impact Journals
ISSN:	1949-2553
Date of First Compliant Deposit:	12 June 2020
Date of Acceptance:	3 June 2020
Last Modified:	05 May 2023 22:33
URI:	https://orca.cardiff.ac.uk/id/eprint/132398

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