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Targeting Mcl-1 by a small molecule NSC260594 for triple-negative breast cancer therapy
Shengli Dong1,2, Margarite D Matossian3, Hassan Yousefi4
1TYK Medicines Inc., Block D, No. 778 Huaxi Avenue, Changxing, 313100, Zhejiang, People's Republic of China. shengli.dong@tykmedicines.com.
Abstract:
Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased apoptosis, which was confirmed by using an Annexin-V/PI assay. Interestingly, NSC260594 treatment reduced the cancer stem cell (CSC) population in TNBCs. To make NSC260594 more clinically relevant, we treated NSC260594 with TNBC cell derived xenograft (CDX) mouse model, and with patient-derived xenograft (PDX) organoids. NSC260594 significantly suppressed MDA-MB-231 tumor growth in vivo, and furthermore, the combination treatment of NSC260594 and everolimus acted synergistically to decrease growth of TNBC PDX organoids. Together, we found that NSC260594 might serve as a lead compound for triple-negative breast cancer therapy through targeting Mcl-1.
Insights
A novel compound, NSC260594, shows potent anti-cancer effects against triple-negative breast cancer (TNBC) by inhibiting Mcl-1. This molecule effectively reduces tumor growth and cancer stem cells, offering a promising new therapeutic lead.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
- Existing treatments for TNBC are limited, highlighting an urgent need for novel therapeutic strategies.
- Myeloid cell leukemia-1 (Mcl-1) is a key protein in cancer cell survival, making it a potential therapeutic target.
Purpose of the Study:
- To identify and evaluate small molecules with cytotoxic activity against TNBC.
- To investigate the mechanism of action of promising compounds, focusing on Mcl-1 inhibition.
- To assess the therapeutic potential of identified compounds in preclinical models of TNBC.
Main Methods:
- Screening of the NCI diversity set IV compound library to identify cytotoxic agents against TNBC.
- In vitro assays to determine dose- and time-dependent cytotoxicity, apoptosis induction (Annexin-V/PI assay), and effects on cancer stem cell populations.
- In vivo studies using TNBC cell-derived xenograft (CDX) mouse models and patient-derived xenograft (PDX) organoids.
- Analysis of Mcl-1 expression and Wnt signaling pathway modulation.
Main Results:
- NSC260594 demonstrated significant dose- and time-dependent cytotoxicity in multiple TNBC cell lines.
- NSC260594 inhibited Mcl-1 expression by downregulating Wnt signaling proteins, leading to increased apoptosis.
- Treatment with NSC260594 reduced the cancer stem cell population in TNBC.
- NSC260594 suppressed tumor growth in a TNBC CDX mouse model and showed synergistic effects with everolimus in TNBC PDX organoids.
Conclusions:
- NSC260594 is a potent inhibitor of Mcl-1 and exhibits significant anti-cancer activity against TNBC.
- NSC260594 reduces tumor burden and cancer stem cells, suggesting its potential as a therapeutic agent for TNBC.
- NSC260594 represents a promising lead compound for developing targeted therapies for triple-negative breast cancer.
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