AVIL inhibitor Compound A (PLH1215) is a specific small molecule actin-binding protein advillin (AVIL)-interacting compound with MST Kd of 6 uM, also blocks AVIL binding to its substrate actin.
Compound A decreased the expression of FOXM1 and LIN28B in GBM cell lines U87 and A172, whereas abundance of AVIL itself was not affected, also also down-regulated at the RNA level of LIN28B.
Compound A killed U87 cell cultures at 10 μM, but TMZ was not effective even at 400 μM.
Compound A effectively kills four GBM cell lines-U87, A172, U251, and T98-at lower IC50 values (10 to 30 μM) than the astrocyte cell line (>120 μM).
Compound A induced a transcriptome profile similar to that of AVIL silencing by siRNA and caused down-regulation of FOXM1 and LIN28B, two known downstream targets of AVIL.
Compound A exhibited selectivity toward tumor cells, sparing astrocytes and neural stem cells in vitro.
Compound A impairs GBM and GBM stem cell growth and migration, extending survival in multiple mouse models of GBM, including TMZ-resistant models.