Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D‐Cys6‐LHRH vedotin, against ovarian cancer cell lines,Chemical Biology & Drug Design

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Cytotoxic activity and cell specificity of a novel LHRH peptide drug conjugate, D‐Cys6‐LHRH vedotin, against ovarian cancer cell lines
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2024-04-15 , DOI: 10.1111/cbdd.14516
Subramanyam Vankadara ₁ , Zhiyuan Ke ₁ , Sifang Wang ₁ , Sin Yun Foo ₂ , Jayantha Gunaratne _{2,

3} , May Ann Lee ₁ , Xiaoying Koh ₁ , C S Brian Chia ₁

Affiliation

Ovarian cancer is the most deadly female gynaecological malignancy in developed countries and new treatments are urgently needed. The luteinising hormone releasing hormone (LHRH) peptide drug conjugate Zoptarelin doxorubicin is one such potential new drug modality that entered clinical trials for treating LHRH receptor‐positive gynaecological cancers. However, development stopped after disappointing Phase 3 results in 2017. We believe the lack of efficacy was due to linker instability and payload potency. In this work, we replaced its linker‐toxin with vedotin (MC‐VC‐PABC‐MMAE), yielding the novel peptide drug conjugate D‐Cys6‐LHRH vedotin. A GI50 and cell specificity comparison against cancerous and non‐cancerous ovarian cell lines showed significantly superior bioactivity and selectivity over Zoptarelin doxorubicin (GI50 4 vs. 453 nM) and other chemotherapeutic drugs used for treating ovarian cancers. Our results suggest D‐Cys6‐LHRH vedotin can potentially be used as a treatment for ovarian cancer.

中文翻译：

新型 LHRH 肽药物缀合物 D-Cys6-LHRH vedotin 针对卵巢癌细胞系的细胞毒活性和细胞特异性

卵巢癌是发达国家最致命的女性妇科恶性肿瘤，迫切需要新的治疗方法。黄体生成素释放激素 (LHRH) 肽药物缀合物 Zoptarelin 阿霉素就是这样一种潜在的新药模式，已进入治疗 LHRH 受体阳性妇科癌症的临床试验。然而，在 2017 年第三阶段结果令人失望后，开发停止了。我们认为缺乏功效是由于链接器不稳定和有效负载效力造成的。在这项工作中，我们用 vedotin (MC-VC-PABC-MMAE) 取代了其连接毒素，产生了新型肽药物缀合物D ‐Cys6-LHRH vedotin。胃肠道50与癌性和非癌性卵巢细胞系的细胞特异性比较显示，与 Zoptarelin 阿霉素（GI 50 4 vs. 453 nM) 和其他用于治疗卵巢癌的化疗药物。我们的结果表明D ‐Cys6-LHRH vedotin 有可能用于治疗卵巢癌。

更新日期：2024-04-15

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