Aminoacyl-tRNA synthetases (ARSs) is an important enzyme and conjugates amino acids to their cognate tRNAs during protein synthesis. In higher eukaryotic systems, ARS-interacting multifunctional proteins (AIMPs) and ARSs form a multisynthetase complex (MSC). The AIMP1−3 provide can guarantee the assembly and the integrity of the MSC.
AIMP2/p38 enhances the growth-arresting signal of TGF-β, at the same time, it promotes cell death by activating p53 and the apoptotic signal of TNF-α. As a result, AIMP2/p38 may play some roles in performing various functions in response to stress signals.
The variant of AIMP2, AIMP2-DX2, is from alternative splicing by the deletion in exon 2. The AIMP2-DX2 loses the ability to associate with the MSC, however, it still inhibits the tumor-suppressive function via competitive interactions with p53, FBP, and TRAF2.
In this article, we will introduce an AIMP2-DX2 inhibitor, BC-DXI-843. We will concisely introduce its properties in vitro and in Vivo.
BC-DXI-843 is a potent and specific AIMP2-DX2 inhibitor with an IC50 of 0.92 μM, more than 100-fold selectivity over AIMP2 (IC50 >100 μM) in a luciferase assay.
In A549 cancer cells and WI-26 normal cells, BC-DXI-843 suppresses cancer cell proliferation in a DX2-dependent manner. The EC50 in A549 cells is 1.20 μM, which is similar to the IC50 for inhibition of DX2. However, no inhibitory results appear in WI-26 cells, suggesting that BC-DXI-843 specifically reduces the viability of cancer cells.
In a 7-week-old female BALB/cSLC-nu/nu mice bearing H460 cells xenograft. BC-DXI-843 declines the embedded-tumor volume gradually. The weight of the tumors after sacrifice decreases in mice after BC-DXI-843 treatment, but it has no changes in body weight.
In conclusion, BC-DXI-843 is a potent AIMP2-DX2 inhibitor. It exhibits the tumor-suppressive function in a DX2-dependent manner via the inhibition of two protein interactions. BC-DXI-843 acts as a promising agent targeting AIMP2-DX2 in lung cancer.
Reference:
Aneesh Sivaraman, et al. J Med Chem. 2020 May 28;63(10):5139-5158.