Abstract
Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.
Highlights
The pyrrolobenzodiazepines (PBDs) are a family of antitumor antibiotics which include the naturally occurring anthramycin, sibiromycin, tomaymycin, the neothramycins and DC-811,2
The current study reports the preclinical pharmacology and mechanism of action of SG3199, confirming the properties which contribute to its success as a novel antibody-drug conjugate (ADC) warhead
SG3199 was synthesised in two steps from monomeric phenol 1, a building block arising during the synthesis of tesirine (Fig. 1B)[18]
Summary
The pyrrolobenzodiazepines (PBDs) are a family of antitumor antibiotics which include the naturally occurring anthramycin, sibiromycin, tomaymycin, the neothramycins and DC-811,2 They exert their biological activity by binding in the minor groove of DNA with a selectivity for 5′-purine-guanine-purine sequences and forming a covalent bond to the exocyclic amino group of the guanine base[3,4]. Synthetic PBD dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, were found to be highly cytotoxic in vitro and to produce DNA interstrand cross-links with high efficiency in both naked DNA and in cells[5,6] Such molecules were shown to span six base pairs in the minor groove of DNA, covalently binding to spatially separated guanines on opposite strands in the central sequence 5′-PuGATCPy-3′ (where Pu is purine and Py is pyrimidine)[7,8]. The current study reports the preclinical pharmacology and mechanism of action of SG3199, confirming the properties which contribute to its success as a novel ADC warhead
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