PT  - JOURNAL ARTICLE
AU  - Kim, Dae Gyu
AU  - Huddar, Srigouri
AU  - Lim, Semi
AU  - Kong, Jiwon
AU  - Lee, Yuno
AU  - Park, Chul Min
AU  - Lee, Seungbeom
AU  - Suh, Young-Ger
AU  - Kim, Minkyoung
AU  - Lee, Kyeong
AU  - Lee, Sunkyung
AU  - Kim, Sunghoon
TI  - Allosteric Inhibition of the Tumor-Promoting Interaction Between Exon 2–Depleted Splice Variant of Aminoacyl–Transfer RNA Synthetase-Interacting Multifunctional Protein 2 and Heat Shock Protein 70
AID  - 10.1124/jpet.121.000766
DP  - 2021 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 358--371
VI  - 379
IP  - 3
4099  - http://jpet.aspetjournals.org/content/379/3/358.short
4100  - http://jpet.aspetjournals.org/content/379/3/358.full
SO  - J Pharmacol Exp Ther2021 Dec 01; 379
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 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.