Although protein-protein interactions (PPIs) have emerged as an attractive therapeutic target space, the identification of chemicals that effectively inhibit PPIs remains challenging. Here, we identified through library screening a chemical probe (compound 1) that can inhibit the tumor-promoting interaction between the oncogenic factor exon 2–depleted splice variant of aminoacyl–transfer RNA synthetase-interacting multifunctional protein 2 (AIMP2-DX2) and heat shock protein 70 (HSP70). We found that compound 1 binds to the N-terminal subdomain of glutathione S-transferase (GST-N) of AIMP2-DX2, causing a direct steric clash with HSP70 and an intramolecular interaction between the N-terminal flexible region and the GST-N of AIMP2-DX2, which induces masking of the HSP70 binding region during molecular dynamics and mutation studies. Compound 1 thus interferes with the AIMP2-DX2 and HSP70 interaction and suppresses the growth of cancer cells that express high levels of AIMP2-DX2 in vitro and in preliminary in vivo experiment. This work provides an example showing that allosteric conformational changes induced by chemicals can be a way to control pathologic PPIs. SIGNIFICANCE STATEMENT Compound 1 is a promising protein-protein interaction inhibitor between AIMP2-DX2 and HSP70 for cancer therapy by the mechanism with allosteric modulation as well as competitive binding. It seems to induce allosteric conformational change of AIMP2-DX2 proteins and direct binding clash between AIMP2-DX2 and HSP70. The compound reduced the level of AIMP2-DX2 in ubiquitin-dependent manner via suppression of binding between AIMP2-DX2 and HSP70 and suppressed the growth of cancer cells highly expressing AIMP2-DX2 in vitro and in preliminary in vivo experiment.
|Number of pages||14|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - 2021 Dec 1|
Bibliographical noteFunding Information:
This work was supported by Global Frontier Project grants [NRF-M3A6A4-2010-0029785 and NRF-2013M3A6A4944802], an IMRCT R grant [NRF-2018R1A5A2023127], NRF-2021R1A3B1076605 of the National Research Foundation of Korea (NRF), SI-1951-30 funded by the Ministry of Science and ICT (MSIT), and the Yonsei University Research Fund [2020-22-0356]. 1D.G.K. and S.H. contributed equally to this work. dx.doi.org/10.1124/jpet.121.000766. S This article has supplemental material available at jpet.aspetjournals.org.
Copyright © 2021 by The Author(s).
All Science Journal Classification (ASJC) codes
- Molecular Medicine