SDL01 is a specific small molecule allosteric modulator / enhancer of the interaction between AIMP2-DX2 (DX2) and Siah1, promotes DX2 degradation by Siah1 with IC50 of 1.09 uM in A549 cells.
SDL01 binds to the pocket surrounding the N-terminal flexible region and GST domain of DX2, causing a conformational change that stabilized its interaction with Siah1.
SDL01 enhanced the direct binding of Siah1, but not that of HSP70, to DX2.
SDL01-induced degradation of DX2 affected cell viability with EC50 of 0.94 uM in A549 cells.
SDL01 effectively reduced the size of the spheroids and induced cytotoxicity in a dose-dependent manner in H460 cells.
SDL01 (40 mg/kg, i.p.) decreased tumor size and weight in xenograft assays using H460 cells, with no significant effect on body weight
SDL01 induced ubiquitination of DX2 at lysine 90, increased Siah1-dependent ubiquitination of the WT DX2 and K7A mutant but not in the K90A mutant。
AIMP2-DX2 (DX2) is an oncogenic variant of aminoacyl-tRNA synthetase-interacting multifunctional protein 2 (AIMP2) that mediates tumorigenic interactions with various factors involved in cancer.