期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 23, 页码 14609-14625出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00873
关键词
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资金
- Epstein Family Foundation
- Sanford Burnham Prebys National Cancer Institute Cancer Center Support Grant [P30 CA030199]
- Larry L. Hillblom Foundation [2019-A-005-NET]
- National Cancer Institute of the National Institutes of Health [T32CA211036]
- SGC - AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN) [875510]
- Janssen
- Merck KGaA (a.k.a. EMD in Canada)
- Merck KGaA (a.k.a. EMD in US)
- Merck Co
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome
- DKTK
- FCI cancer network
- DFG [SFB1177]
- 2019 Pancreatic Cancer Action Network Translational Research Grant [19-65COSF]
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.
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