Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy

Sunghoon Kim, Aneesh Sivaraman, Dae Gyu Kim, Deepak Bhattarai, Minkyoung Kim, Hwa Young Lee, Semi Lim, Jiwon Kong, Ja-Il Goo, Seunghwan Shim, Seungbeom Lee, Young-Ger Suh, Yongseok Choi, Kyeong Lee

Research output: Contribution to journalArticle

Abstract

AIMP2-DX2, a splicing variant of AIMP2, is up-regulated in lung cancer, possesses oncogenic activity, and results in tumorigenesis. Specifically inhibiting the interaction between AIMP2-DX2 and HSP70 to suppress AIMP2-DX2-dependent cancers with small molecules is considered a promising avenue for cancer therapeutics. Optimization of hit BC-DXI-04 (IC50 = 40.1 μM) provided new potent sulfonamide based AIMP2-DX2 inhibitors. Among these, BC-DXI-843 showed improved inhibition against AIMP2-DX2 (IC50 = 0.92 μM) with more than 100-fold selectivity over AIMP2 in a luciferase assay. Several binding assays indicated that this compound effectively induces cancer cell apoptosis by specifically interrupting the interaction between DX2 and HSP70, which leads to the degradation of DX2 via Siah1-mediated ubiquitination. More importantly, BC-DXI-843 demonstrated in vivo efficacy in a tumor xenograft mouse model (H460 cells) at a dosage of 50 mg/kg, suggesting it as a promising lead for development of novel therapeutics targeting AIMP2-DX2 in lung cancer.
Original languageEnglish
Pages (from-to)5139-5158
JournalJournal of Medicinal Chemistry
Volume63
Issue number10
DOIs
Publication statusPublished - 2020 May 28

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    Kim, S., Sivaraman, A., Kim, D. G., Bhattarai, D., Kim, M., Lee, H. Y., Lim, S., Kong, J., Goo, J-I., Shim, S., Lee, S., Suh, Y-G., Choi, Y., & Lee, K. (2020). Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy. Journal of Medicinal Chemistry, 63(10), 5139-5158. https://doi.org/10.1021/acs.jmedchem.9b01961.