Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody-Drug Conjugates (ADCs)

被引：11

作者：

Archer, Katie E. ^{[1
]}

Reid, Emily E. ^{[1
]}

Shizuka, Manami ^{[1
,2
]}

Woods, James ^{[1
,3
]}

Harris, Luke ^{[1
]}

Maloney, Erin K. ^{[1
]}

Bartle, Laura M. ^{[1
]}

Ab, Olga ^{[1
]}

Wilhelm, Alan ^{[1
]}

Setiady, Yulius ^{[1
]}

Ponte, Jose F. ^{[1
]}

Singh, Rajeeva ^{[1
]}

Keating, Thomas A. ^{[1
]}

Chari, Ravi V. J. ^{[1
]}

Miller, Michael L. ^{[1
]}

机构：

[1] ImmunoGen Inc, 830 Winter St, Waltham, MA 02451 USA

[2] Pharmaron Inc, Waltham, MA 02451 USA

[3] Alkermes Inc, Waltham, MA 02451 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 08期

关键词：

Antibody-drug conjugates; ADCs; indolinobenzodiazepines; CANCER;

D O I：

10.1021/acsmedchemlett.9b00254

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：1211 / 1215

页数：9