TY - JOUR
T1 - Synthesis and Structure-Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy
AU - Sivaraman, Aneesh
AU - Kim, Dae Gyu
AU - Bhattarai, Deepak
AU - Kim, Minkyoung
AU - Lee, Hwa Young
AU - Lim, Semi
AU - Kong, Jiwon
AU - Goo, Ja Il
AU - Shim, Seunghwan
AU - Lee, Seungbeom
AU - Suh, Young Ger
AU - Choi, Yongseok
AU - Kim, Sunghoon
AU - Lee, Kyeong
N1 - Funding Information:
This study was funded with a National Research Foundation of Korea (NRF) grant funded by the Korea Government (MSIT) (Grants NRF 2018R1A5A2023127 and NRF-M3A6A4-2010-0029785).
PY - 2020/5/28
Y1 - 2020/5/28
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.9b01961
DO - 10.1021/acs.jmedchem.9b01961
M3 - Article
C2 - 32315177
AN - SCOPUS:85084092035
VL - 63
SP - 5139
EP - 5158
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -