PT  - JOURNAL ARTICLE
AU  - Dae Gyu Kim
AU  - Srigouri Huddar
AU  - Semi Lim
AU  - Jiwon Kong
AU  - Yuno Lee
AU  - Chul Min Park
AU  - Seungbeom Lee
AU  - Young-Ger Suh
AU  - Minkyoung Kim
AU  - Kyeong Lee
AU  - Sunkyung Lee
AU  - Sunghoon Kim
TI  - Allosteric Inhibition of the Tumor-Promoting Interaction between AIMP2-DX2 and HSP70
AID  - 10.1124/jpet.121.000766
DP  - 2021 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2021-000766
4099  - http://jpet.aspetjournals.org/content/early/2021/09/09/jpet.121.000766.short
4100  - http://jpet.aspetjournals.org/content/early/2021/09/09/jpet.121.000766.full
AB  - 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 AIMP2-DX2 and 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 (NFR) 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.