1. 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.
- Author
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Ren H, Bakas NA, Vamos M, Chaikuad A, Limpert AS, Wimer CD, Brun SN, Lambert LJ, Tautz L, Celeridad M, Sheffler DJ, Knapp S, Shaw RJ, and Cosford NDP
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Screening Assays, Antitumor, Drug Synergism, Female, HEK293 Cells, Humans, Mice, Inbred C57BL, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemical synthesis, Triple Negative Breast Neoplasms drug therapy, Antineoplastic Agents pharmacology, Autophagy drug effects, Autophagy-Related Protein-1 Homolog antagonists & inhibitors, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Phthalazines pharmacology, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
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.
- Published
- 2020
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