Page 20 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-11]

Synthesis, and structure-activity relationships of aryl

sulfonamide based small molecule AIMP2-DX2 inhibitors as

potential cancer therapeutics

Aneesh Sivaraman¹˙#, Dae Gyu Kim²˙#, Minkyoung Kim¹, Sunghoon Kim²˙*, Kyeong Lee¹˙*

¹College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea, ²College of Pharmacy &

College of Medicine, Yonsei University, Incheon 21983, Republic of Korea

The tumorigenic factor AIMP2-DX2, AIMP2 lacking exon 2, is often up regulated in many cancers. Specific inhibition
of the interaction between AIMP2-DX2 and HSP70 with small molecules provides a promising therapeutic strategy

for AIMP2-DX2-dependent cancers. A structure-activity relationship study using a sulfonamide hit compound (BC-
DXI-04, IC50 = 40.14 μM) led to the preparation of several novel aryl sulfonamides as 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. 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, the compound demonstrated in vivo efficacy in a tumor xenograft mouse model

(H460 cells) at a dosage of 50 mg/kg. Collectively, these findings indicate that BC-DXI-843 is a promising lead for
the development of novel therapeutics targeting AIMP2-DX2 in lung cancer.