Modification of the duocarmycin pharmacophore enables CYP1A1 targeting for biological activity

Abstract

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Antitumor Activity of a Duocarmycin Analogue Rationalized to Be Metabolically Activated by Cytochrome P450 1A1 in Human Transitional Cell Carcinoma of the Bladder

“…Together these data indicate that clinical bladder cancer could be specifically chemosensitized to ICT2700, a synthetic derivative of the ultrapotent duocarmycins that we have shown to be metabolically activated by CYP1A1 (19).…”

“…Efficacy against CYP1A1-expressing tumors, but not CYP1A1-null tumors provides compelling evidence for the importance of CYP1A1 in formation of a cytotoxic metabolite in vivo. The antitumor efficacy of the authentic metabolite ICT2740 has been shown previously to involve DNAalkylation (19). Importantly, although both ICT2700 and its authentic metabolite ICT2740 have shown potent antitumor activity in vivo, only ICT2740 administration was associated with body weight loss, an indicator of normal tissue toxicity.…”

“…We have synthesized a truncated chloromethylpyrroloindoline (ICT2700), which we have shown to undergo CYP1A1-mediated oxidation, resulting in production of a potent and highly specific DNA minor groove alkylating agent (19). In this study, we identify CYP1A1 expression in human bladder cancer and address the potential for CYP1A1-activated therapy based on the ultrapotent duocarmycins by showing, for the first time, CYP1A1 selective efficacy of ICT2700.…”

“…2) was synthesized in-house and shown to be authentic and greater than 97% pure (19). For cellular analyses, the compound was prepared as a 10 mmol/L stock solution in dimethyl sulfoxide (DMSO).…”

Probing cytochrome P450-mediated activation with a truncated azinomycin analogue

“…Certain isoforms, notably CYP1A1, 1B1 and 3A4 are identified as highly expressed in certain tumours 10 indicating the value of truncated azinomycin analogues as potential bioprecursors with chemotherapeutic efficacy. We have demonstrated proof of principle with bioprecursors of the duocarmycin natural products targeting CYP1A1 19,20 and 2W1 14,21 enzymes. Uniquely, we have demonstrated that CYP selective bioactivation in vivo can be obtained with no overt toxicity to normal tissues including the liver.…”