Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs).,ACS Medicinal Chemistry Letters

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Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs).
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-07-22 00:00:00 , DOI: 10.1021/acsmedchemlett.9b00254
Katie E Archer ₁ , Emily E Reid ₁ , Manami Shizuka ₁ , James Woods ₁ , Luke Harris ₁ , Erin K Maloney ₁ , Laura M Bartle ₁ , Olga Ab ₁ , Alan Wilhelm ₁ , Yulius Setiady ₁ , Jose F Ponte ₁ , Rajeeva Singh ₁ , Thomas A Keating ₁ , Ravi V J Chari ₁ , Michael L Miller ₁

Affiliation

Indolinobenzodiazepine DNA alkylators (IGNs) are the cytotoxic payloads in antibody–drug conjugates (ADCs) currently undergoing Phase I clinical evaluation (IMGN779, IMGN632, and TAK164). These ADCs possess linkers that have been incorporated into a central substituted phenyl spacer. Here, we present an alternative strategy for the IGNs, linking through a carbamate at the readily available N-10 amine present in the monoimine containing dimer. As a result, we have designed a series of N-10 linked IGN ADCs with a wide range of in vitro potency and tolerability, which may allow us to better match an IGN with a particular target based on the potential dosing needs.

中文翻译：

高强度N-10氨基连接的DNA烷基化的吲哚苯并二氮杂卓抗体-药物缀合物（ADCs）的合成。

吲哚并二氮杂卓DNA烷基化剂（IGN）是抗体-药物偶联物（ADC）中目前正在接受I期临床评估（IMGN779，IMGN632和TAK164）的细胞毒性有效载荷。这些ADC具有连接器，这些连接器已并入中央取代的苯基间隔基中。在这里，我们提出了一种IGNs的替代策略，即通过氨基甲酸酯与含单亚胺的二聚体中存在的N-10胺连接。因此，我们设计了一系列N-10链接的IGN ADC，具有广泛的体外效价和耐受性，这可以使我们根据潜在的剂量需求更好地将IGN与特定目标相匹配。

更新日期：2019-07-22

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