Entwicklung Pyrrolobenzodiazepin(PBD)-haltiger Antikörper-Wirkstoff-Konjugate (ADCs) ausgehend von Anthramycin

Julia Mantaj; Paul J.M.  Jackson; Khondaker M. Rahman; David E. Thurston

doi:10.1002/ange.201510610

Entwicklung Pyrrolobenzodiazepin(PBD)-haltiger Antikörper-Wirkstoff-Konjugate (ADCs) ausgehend von Anthramycin

Translated title of the contribution: Development of pyrrolobenzodiazepine (PBD)-containing antibody-drug conjugates (ADCs) starting from anthramycin

Julia Mantaj, Paul J.M. Jackson, Khondaker M. Rahman, David E. Thurston

Human Sciences (352)

Research output: Contribution to journal › Article › peer-review

Abstract

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective drugs that bind to the minor groove of DNA and form a covalent aminal bond between the C11 position and the C2-NH 2 groups of the guanine bases. Anthramycin is the first example of a PBD monomer and was discovered in the 1960s. The best-known PBD dimer, SJG-136, was developed in the 1990s and has now already completed phase II clinical trials in patients with leukemia and ovarian cancer. Recently, antibody-drug conjugates (ADCs) have been produced from PBD dimer analogues and antibodies that specifically bind to tumor cells. Several of these are currently in clinical trials and many others are in preclinical development. This review shows the evolution of PBDs from anthramycin through the first PBD dimers to PBD-containing ADCs and covers both the structure-activity relationships and biology of PBDs as well as the strategies for their use as drug components in ADCs.

Translated title of the contribution	Development of pyrrolobenzodiazepine (PBD)-containing antibody-drug conjugates (ADCs) starting from anthramycin
Original language	German
Journal	Angewandte Chemie
DOIs	https://doi.org/10.1002/ange.201510610
Publication status	Published - 9 Jan 2017

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Angewandte Chemie - 2016 - Mantaj - Entwicklung Pyrrolobenzodiazepin PBD ‐haltiger Antik rper‐Wirkstoff‐Konjugate ADCs Final published version, 6.36 MBLicence: CC BY-NC-ND 4.0

Cite this

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title = "Entwicklung Pyrrolobenzodiazepin(PBD)-haltiger Antik{\"o}rper-Wirkstoff-Konjugate (ADCs) ausgehend von Anthramycin",

abstract = "The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective drugs that bind to the minor groove of DNA and form a covalent aminal bond between the C11 position and the C2-NH 2 groups of the guanine bases. Anthramycin is the first example of a PBD monomer and was discovered in the 1960s. The best-known PBD dimer, SJG-136, was developed in the 1990s and has now already completed phase II clinical trials in patients with leukemia and ovarian cancer. Recently, antibody-drug conjugates (ADCs) have been produced from PBD dimer analogues and antibodies that specifically bind to tumor cells. Several of these are currently in clinical trials and many others are in preclinical development. This review shows the evolution of PBDs from anthramycin through the first PBD dimers to PBD-containing ADCs and covers both the structure-activity relationships and biology of PBDs as well as the strategies for their use as drug components in ADCs.",

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AU - Rahman, Khondaker M.

AU - Thurston, David E.

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N2 - The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective drugs that bind to the minor groove of DNA and form a covalent aminal bond between the C11 position and the C2-NH 2 groups of the guanine bases. Anthramycin is the first example of a PBD monomer and was discovered in the 1960s. The best-known PBD dimer, SJG-136, was developed in the 1990s and has now already completed phase II clinical trials in patients with leukemia and ovarian cancer. Recently, antibody-drug conjugates (ADCs) have been produced from PBD dimer analogues and antibodies that specifically bind to tumor cells. Several of these are currently in clinical trials and many others are in preclinical development. This review shows the evolution of PBDs from anthramycin through the first PBD dimers to PBD-containing ADCs and covers both the structure-activity relationships and biology of PBDs as well as the strategies for their use as drug components in ADCs.

AB - The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a family of sequence-selective drugs that bind to the minor groove of DNA and form a covalent aminal bond between the C11 position and the C2-NH 2 groups of the guanine bases. Anthramycin is the first example of a PBD monomer and was discovered in the 1960s. The best-known PBD dimer, SJG-136, was developed in the 1990s and has now already completed phase II clinical trials in patients with leukemia and ovarian cancer. Recently, antibody-drug conjugates (ADCs) have been produced from PBD dimer analogues and antibodies that specifically bind to tumor cells. Several of these are currently in clinical trials and many others are in preclinical development. This review shows the evolution of PBDs from anthramycin through the first PBD dimers to PBD-containing ADCs and covers both the structure-activity relationships and biology of PBDs as well as the strategies for their use as drug components in ADCs.

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