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 Ren; Nicole A Bakas; Mitchell Vamos; Apirat Chaikuad; Allison S Limpert; Carina D Wimer; Sonja N Brun; Lester J Lambert; Lutz Tautz; Maria Celeridad; Douglas J Sheffler; Stefan Knapp; Reuben J Shaw; Nicholas D P Cosford

doi:10.1021/acs.jmedchem.0c00873

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. doi: 10.1021/acs.jmedchem.0c00873. Epub 2020 Nov 17.

Authors

Affiliations

¹ Cancer Molecules & Structures Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.
² Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Frankfurt 60438, Germany.
³ Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt 60438, Germany.
⁴ Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, San Diego, California 92037, United States.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Autophagy / drug effects*
Autophagy-Related Protein-1 Homolog / antagonists & inhibitors*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Screening Assays, Antitumor
Drug Synergism
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Mice, Inbred C57BL
Phthalazines / pharmacology*
Piperazines / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors
Pyrimidines / chemical synthesis
Pyrimidines / pharmacology*
Triple Negative Breast Neoplasms / drug therapy

Substances

Antineoplastic Agents
Intracellular Signaling Peptides and Proteins
Phthalazines
Piperazines
Poly(ADP-ribose) Polymerase Inhibitors
Protein Kinase Inhibitors
Pyrimidines
Autophagy-Related Protein-1 Homolog
Protein Serine-Threonine Kinases
ULK1 protein, human
Ulk2 protein, human
olaparib

Abstract

Publication types

MeSH terms

Substances

Grants and funding