Autophagy is a multi-step pathway initiated through the ULK preinitiation complex, which consists of unc-51-like autophagy activating kinase 1 (ULK1) or its homologue ULK2, autophagy-related protein 13 (ATG13), ATG101 and focal adhesion kinase (FAK) family-interacting protein (FIP200). AMP-activated protein kinase (AMPK) activates autophagy by inhibiting mTOR activity via phosphorylation of the mTOR complex components raptor and tuberous sclerosis complex 2 (TSC2). Conversely, mTOR suppresses autophagy by directly phosphorylating and inhibiting the ULK1/2 function.
ULK1/2 plays crucial roles in autophagy by phosphorylating ATG13, ATG101, and FIP200 and proteins in the downstream Beclin1 initiation complex: Beclin1, VPS34, ATG9, and ATG16L1. SBP-7455 is an orally active dual-specific ULK1/2 autophagy inhibitor. Moreover, SBP-7455 potently inhibits ULK1/2 enzymatic activity in vitro and in cells.
SBP-7455 promotes apoptosis in triple-negative breast cancer cells under nutrient-deprived conditions. Treatment of starved cells with SBP-7455 significantly reduces the mCherry:GFP ratio, indicating inhibition of the starvation-induced increase in autophagic flux. SBP-7455 reduces the viability of triple-negative breast cancer cells and has oral bioavailability in mice. Furthermore, SBP-7455 inhibits Starvation-induced autophagic flux in triple-negative breast cancer cells. SBP-7455 selectively blocks autophagic flux in human triple-negative breast cancer cell lines. In addition, SBP-7455 acts synergistically with PARP inhibitors to kill triple-negative breast cancer cells. These results suggest that combination therapy with ULK1/2 inhibitors may have utility for the treatment of drug-resistant TNBC. Besides, SBP-7455 reverses Olaparib-induced upregulation of autophagic flux in triple-negative breast cancer Cells
In summary, SBP-7455 is a highly effective inhibitor of phosphorylation of the ULK1, for the treatment of triple-negative breast cancer.
Huiyu Ren, et al. Design, Synthesis, and Characterization of an Orally Active Dual-Specific ULK1/2 Autophagy Inhibitor that Synergizes with the PARP Inhibitor Olaparib for the Treatment of Triple-Negative Breast Cancer. J Med Chem. 2020 Dec 10;63(23):14609-14625.