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Discovery of novel quinoline scaffold selective estrogen receptor degraders (SERDs) for treatment of ER positive breast cancer with enhanced antiproliferative bioactivity through immunogenic cell death (ICD) effects.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Sep 05; Vol. 275, pp. 116534. Date of Electronic Publication: 2024 May 27. - Publication Year :
- 2024
-
Abstract
- Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Humans
Female
Structure-Activity Relationship
Molecular Structure
Animals
Immunogenic Cell Death drug effects
Drug Discovery
Dose-Response Relationship, Drug
MCF-7 Cells
Mice
Endoplasmic Reticulum Stress drug effects
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Breast Neoplasms metabolism
Cell Proliferation drug effects
Quinolines pharmacology
Quinolines chemistry
Quinolines chemical synthesis
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Receptors, Estrogen metabolism
Drug Screening Assays, Antitumor
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 275
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38870830
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116534