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

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posted on 2023-06-07, 07:16 authored by Leanne Milton-Harris, Mark Jeeves, Sarah A Walker, Simon E Ward, Erika ManciniErika Mancini
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Oncotarget

ISSN

1949-2553

Publisher

Impact Journals

Volume

11

Page range

1737-1748

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Haematology Research Group Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2020-06-17

First Open Access (FOA) Date

2020-06-17

First Compliant Deposit (FCD) Date

2020-06-17

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