Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody-Drug Conjugates (ADCs).,ACS Medicinal Chemistry Letters

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Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody-Drug Conjugates (ADCs).
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-07-10 00:00:00 , DOI: 10.1021/acsmedchemlett.9b00240
Emily E Reid ₁ , Katie E Archer ₁ , Manami Shizuka ₁ , Alan Wilhelm ₁ , Nicholas C Yoder ₁ , Chen Bai ₁ , Nathan E Fishkin ₁ , Luke Harris ₁ , Erin K Maloney ₁ , Paulin Salomon ₁ , Erica Hong ₁ , Rui Wu ₁ , Olga Ab ₁ , Shan Jin ₁ , Katharine C Lai ₁ , Surina Sikka ₁ , Ravi V J Chari ₁ , Michael L Miller ₁

Affiliation

Antibody–drug conjugates (ADCs) that incorporate potent indolinobenzodiazepine DNA alkylators as the payload component are currently undergoing clinical evaluation. In one ADC design, the payload molecules are linked to the antibody through a peptidase-labile l-Ala-l-Ala linker. In order to determine the role of amino acid stereochemistry on antitumor activity and tolerability, we incorporated l- and d-alanyl groups in the dipeptide, synthesized all four diastereomers, and prepared and tested the corresponding ADCs. Results of our preclinical evaluation showed that the l-Ala-l-Ala configuration provided the ADC with the highest therapeutic index (antitumor activity vs toxicity).

中文翻译：

接头立体化学对吲哚并苯并二氮杂Contain抗体-药物缀合物（ADC）活性的影响。

结合有效的吲哚基二氮杂卓DNA烷基化剂作为有效载荷成分的抗体-药物偶联物（ADC）目前正在临床评估中。在一个ADC设计中，有效负载分子通过肽酶不稳定的连接到抗体升-Ala-升-Ala接头。为了确定氨基酸立体化学对抗肿瘤活性和耐受性的作用，我们在二肽中掺入了l和d-丙氨酰基，合成了所有四种非对映异构体，并制备并测试了相应的ADC。我们的临床前评估结果表明，l- Ala- 1 -Ala构型为ADC提供了最高的治疗指数（抗肿瘤活性与毒性）。

更新日期：2019-07-10

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