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Development of a Highly Selective Ferroptosis Inducer Targeting GPX4 with 2-Ethynylthiazole-4-carboxamide as
Sunkai Gu1, Guanyu Yang1, Hongyuan Bian1
1Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
Abstract:
A highly selective ferroptosis inducer with drug-like properties can significantly advance the research on inducing ferroptosis for anticancer treatment. We previously reported a highly active GPX4 inhibitor 26a, but its activity and stability need further improvement. In this work, a novel GPX4 inhibitor ()-9i with more potent cytotoxicity (IC50 = 0.0003 μM against HT1080) and ferroptosis selectivity (selectivity index = 24933) was gained via further electrophilic warhead screening and structure-based optimization. The cellular thermal shift assay (CETSA) indicated that ()-9i could stabilize GPX4 with a Tm value of 6.2 °C. Furthermore, ()-9i showed strong binding affinity against GPX4 (KD = 20.4 nM). More importantly, ()-9i has more favorable pharmacokinetic properties than 26a, which endowed ()-9i with potential in antitumor research and as a tool drug for further study of ferroptosis. Associated with these, ()-9i treatment significantly inhibited tumor growth in the xenograft tumor mouse model without detectable toxicity.
Insights
Researchers developed a novel GPX4 inhibitor, ( )-9i, demonstrating potent anticancer activity and high selectivity for inducing ferroptosis. This compound shows promise as a therapeutic agent and research tool for ferroptosis-driven cancer treatments.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Ferroptosis, a regulated form of cell death, presents a promising avenue for anticancer therapies.
- Developing highly selective ferroptosis inducers with drug-like properties is crucial for advancing this field.
- Previous GPX4 inhibitor 26a showed activity but required improved potency and stability.
Purpose of the Study:
- To design and synthesize a novel, highly potent, and selective GPX4 inhibitor for inducing ferroptosis.
- To evaluate the compound's anticancer activity, selectivity, and pharmacokinetic properties.
- To assess the therapeutic potential of the novel inhibitor in preclinical cancer models.
Main Methods:
- Structure-based optimization and electrophilic warhead screening were employed to identify novel GPX4 inhibitors.
- Cytotoxicity was assessed using IC50 values against HT1080 cells.
- Cellular thermal shift assay (CETSA) and binding affinity studies (KD) were performed to characterize GPX4 interaction.
- Pharmacokinetic properties were evaluated and compared to a previous inhibitor.
- In vivo efficacy was tested using a xenograft tumor mouse model.
Main Results:
- A novel GPX4 inhibitor, ( )-9i, was synthesized with significantly enhanced cytotoxicity (IC50 = 0.0003 μM) and ferroptosis selectivity (selectivity index = 24933).
- ( )-9i demonstrated GPX4 stabilization (Tm = 6.2 °C) and strong binding affinity (KD = 20.4 nM).
- The compound exhibited improved pharmacokinetic properties compared to the previous inhibitor 26a.
- In vivo studies showed significant inhibition of tumor growth in a xenograft mouse model with no detectable toxicity.
Conclusions:
- The novel GPX4 inhibitor ( )-9i is a highly potent and selective inducer of ferroptosis with favorable drug-like properties.
- ( )-9i demonstrates significant antitumor efficacy in vivo without observable toxicity, suggesting its potential as an anticancer therapeutic.
- This compound serves as a valuable tool for further research into ferroptosis mechanisms and therapeutic strategies.
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