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

Inhibition of autophagy, the major cellular recycling pathway in mammalian cells, is a promising strategy for the treatment of triple-negative breast cancer (TNBC). We previously reported SBI-0206965, a small molecule inhibitor of unc-51-like autophagy activating kinase 1 (ULK1), which is a key regulator of autophagy initiation. Herein, we describe the design, synthesis, and characterization of new dual inhibitors of ULK1 and ULK2 (ULK1/2). One inhibitor, SBP-7455 (compound 26), displayed improved binding affinity for ULK1/2 compared with SBI-0206965, potently inhibited ULK1/2 enzymatic activity in vitro and in cells, reduced the viability of TNBC cells and had oral bioavailability in mice. SBP-7455 inhibited starvation-induced autophagic flux in TNBC cells that were dependent on autophagy for survival and displayed synergistic cytotoxicity with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib against TNBC cells. These data suggest that combining ULK1/2 and PARP inhibition may have clinical utility for the treatment of TNBC.

 

Comments:

This sounds like an exciting development! Inhibiting autophagy, especially through the targeting of ULK1 and ULK2, seems to hold promise for treating triple-negative breast cancer (TNBC). SBP-7455, as a dual inhibitor of ULK1/2, appears to be an advancement over the previous SBI-0206965, showing improved binding affinity and potent inhibition of ULK1/2 activity both in vitro and in cells. Additionally, its ability to reduce TNBC cell viability and its oral bioavailability in mice are encouraging findings.

The inhibition of starvation-induced autophagic flux in TNBC cells, especially those reliant on autophagy for survival, indicates the potential of SBP-7455 as a targeted therapeutic agent. Moreover, the observed synergistic cytotoxicity of SBP-7455 with olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, against TNBC cells further supports the idea of combining ULK1/2 and PARP inhibition for potential clinical utility in treating TNBC.

The ability to combine therapies effectively is crucial in addressing cancer, especially in cases like TNBC, where treatment options may be limited. This approach could offer a new avenue for treatment strategies, potentially improving patient outcomes. It's a promising step forward in the field of cancer therapeutics!

Related Products

Cat.No.	Product Name	Information
S3393	SBP-7455	SBP-7455 is a dual-Specific ULK1/2 autophagy inhibitor with IC50s of 13 nM and 476 nM for ULK1 and ULK2 in ADP-Glo assay, respectively.

Related Targets

ULK