Open AccessDesign, 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(s) -
Huiyu Ren,
Nicole A. Bakas,
Mitchell Vamos,
A. Chaikuad,
Allison S. Limpert,
Carina Wimer,
Sonja N. Brun,
Lester J. Lambert,
Lutz Tautz,
Maria Celeridad,
Douglas J. Sheffler,
Stefan Knapp,
Reuben J. Shaw,
Nicholas D. P. Cosford
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c00873
Subject(s) - parp inhibitor , autophagy , olaparib , chemistry , cancer research , ulk1 , triple negative breast cancer , poly adp ribose polymerase , pharmacology , kinase , cancer , breast cancer , biochemistry , enzyme , protein kinase a , biology , polymerase , medicine , ampk , apoptosis
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.