ELMO2 inhibitor C52 is a specific small-molecule Engulfment and cell motility 2 (ELMO2) inhibitor, binds to ELMO2 with a dissociation constant (KD) of 1.0 uM, effectively kills ELMO3-low lung cancer cells and EGFR inhibitor-resistant cells.
C52 shows no binding was observed with the ELMO2 His435Ala (H435A) mutant, suggesting the critical role of HIS-435 in the interaction.
C52 specifically suppressed the viability of mesenchymal ARTICLE IN PRESS ARTICLE IN PRESS like cells compared with epithelial-like cells.
ELMO3 over-expression rescued the cell death phenotype induced by C52 treatment.
Similar to ELMO2 knockdown, C52 suppressed FAK phosphorylation in a concentration-dependent and time-dependent manner, induced autophagy-dependent cell death in NCI-H1299 and A549.
C52 exhibited a significant synergistic effect for suppression lung cancer cell proliferation with FAK inhibitor Defactinib.
C52 significantly suppressed tumor growth in mesenchymal-like A549 xenograft mice, but showed no significant growth inhibition in epithelial-like PC-9 xenograft mice, also failed to suppress the growth of tumors expressing the ELMO2-H435A mutant in vivo.