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

ABSTRACT: 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.

SUBMITTER: Archer KE

PROVIDER: S-EPMC6691681 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Archer Katie E KE Reid Emily E EE Shizuka Manami M Woods James J Harris Luke L Maloney Erin K EK Bartle Laura M LM Ab Olga O Wilhelm Alan A Setiady Yulius Y Ponte Jose F JF Singh Rajeeva R Keating Thomas A TA Chari Ravi V J RVJ Miller Michael L ML

ACS medicinal chemistry letters 20190722 8

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 ...[more]

PMID: 31413807

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