Developing a Tanshinone IIA Memetic by Targeting MIOS to Regulate mTORC1 and Autophagy in Glioblastoma

Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of Glioblastoma multiforme (GBM), with a range of molecular mechanisms including inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but this pathway has not been investigated regarding autophagy. Here we employed the model system Dictyostelium discoideum and GBM cell lines to investigate the role of T2A in autophagy induction, focusing on the regulation of SESN via a GATOR2 component MIOS, to mTORC1. We show that in D. discoideum, T2A treatment induces autophagy, and both this effect and mTORC1 inhibition is lost upon ablation of either SESN (sesn-) or MIOS (mios-). We then investigated targeting MIOS to reproduce this effect of T2A. Here, computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, and one compound (MIOS inhibitor 3; Mi3) that reduced cell proliferation in two GBM cell lines. Furthermore, Mi3 specificity was demonstrated through the reduction of D. discoideum cell proliferation and induced autophagy, dependent upon MIOS. These effects were also confirmed in GBM cells, where Mi3 treatment also inhibited mTORC1 activity and induced autophagy. Thus, we identify a potential T2A mimetic with demonstrated effects on inhibition of mTORC1 and induction of autophagy in GBM cells.