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Discovery of AL-GDa62 as a Potential Synthetic Lethal Lead for the Treatment of Gastric Cancer
Andreas Luxenburger1, Nicola Bougen-Zhukov2, Michael G Fraser1
1Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand.
Abstract:
Diffuse gastric cancer and lobular breast cancer are aggressive malignancies that are frequently associated with inactivating mutations in the tumor suppressor gene CDH1. Synthetic lethal (SL) vulnerabilities arising from CDH1 dysfunction represent attractive targets for drug development. Recently, SLEC-11 (1) emerged as a SL lead in E-cadherin-deficient cells. Here, we describe our efforts to optimize 1. Overall, 63 analogues were synthesized and tested for their SL activity toward isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1). Among the 26 compounds with greater cytotoxicity, AL-GDa62 (3) was four-times more potent and more selective than 1 with an EC50 ratio of 1.6. Furthermore, 3 preferentially induced apoptosis in CDH1 cells, and Cdh1 mammary and gastric organoids were significantly more sensitive to 3 at low micromolar concentrations. Thermal proteome profiling of treated MCF10A-CDH1 cell protein lysates revealed that 3 specifically inhibits TCOF1, ARPC5, and UBC9. In vitro, 3 inhibited SUMOylation at low micromolar concentrations.
Insights
Researchers optimized a synthetic lethal compound (SLEC-11) to target CDH1-deficient cancers. The new compound, AL-GDa62, shows increased potency and selectivity, inducing apoptosis in cancer cells and organoids by inhibiting specific proteins involved in SUMOylation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Diffuse gastric and lobular breast cancers are aggressive malignancies often linked to CDH1 gene mutations.
- CDH1 dysfunction creates synthetic lethal vulnerabilities, presenting therapeutic targets.
- SLEC-11 was identified as a synthetic lethal lead compound for CDH1-deficient cells.
Purpose of the Study:
- To optimize the synthetic lethal compound SLEC-11 for enhanced efficacy against CDH1-deficient cancers.
- To identify novel therapeutic agents targeting E-cadherin-deficient malignancies.
Main Methods:
- Synthesis and testing of 63 analogues of SLEC-11 for synthetic lethal activity.
- Cytotoxicity assays using isogenic mammary epithelial CDH1-deficient cells (MCF10A-CDH1).
- Thermal proteome profiling to identify compound targets and in vitro SUMOylation assays.
Main Results:
- AL-GDa62 (compound 3) demonstrated four-times greater potency and selectivity than SLEC-11.
- Compound 3 preferentially induced apoptosis in CDH1-deficient cells and organoids at low micromolar concentrations.
- AL-GDa62 was found to inhibit TCOF1, ARPC5, and UBC9, and inhibit SUMOylation in vitro.
Conclusions:
- AL-GDa62 represents a promising, optimized therapeutic candidate for CDH1-deficient cancers.
- Targeting synthetic lethality through compounds like AL-GDa62 offers a viable strategy for treating these aggressive cancers.
- The identified protein targets and mechanism of action provide a foundation for further drug development.
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