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.
Huiyu RenNicole A BakasMitchell VamosApirat ChaikuadAllison S LimpertCarina D WimerSonja N BrunLester J LambertLutz TautzMaria CeleridadDouglas J ShefflerStefan KnappReuben J ShawNicholas D P CosfordPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- induced apoptosis
- cell death
- endoplasmic reticulum stress
- cell cycle arrest
- signaling pathway
- oxidative stress
- small molecule
- dna damage
- dna repair
- type diabetes
- adipose tissue
- transcription factor
- machine learning
- big data
- tyrosine kinase
- nitric oxide
- insulin resistance
- drug induced
- binding protein
- dna binding
- deep learning
- protein kinase