DS-1-38 (EYA1 inhibits DS38) is a small molecule allosteric inhibitor of EYA proteins and sonic hedgehog (SHH) signaling pathway, binds to EYA1 and inhibits EYA1 phosphatase activity.
DS38 (10 uM) significantly suppresses the SAG-induced GLI activation in SHH-MB model cell line.
DS38 inhibits cell viability of Daoy, a human medulloblastoma cell line derived from a SHH-MB, as well as TOV112, a human ovarian cell line with highly activated SHH signaling (EC50 of 11.12 uM and 5.98 uM, respectively).
DS38 reduces phosphatase activity of EYA1, does not affect the interaction of EYA1 with the cotranscription factor SIX1, nor alter the subcellular localization of EYA1.
DS38 significantly increased pYp-H2AX expression in SL2 cells exposed to SAG.
DS38 binds to full-length EYA1 with Kd of 76 uM.
DS38 inhibits SHH activation and proliferation while activating a DNA damage response, shows therapeutic potential in cells resistant to SMO receptor antagonists.
DS38 (20 mg/kg) showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB.