title: Re-engineering of the duocarmycin structural architecture enables bioprecursor development targeting CYP1A1 and CYP2W1 for biological activity.
abstract: A library of duocarmycin bioprecursors based on the CPI and CBI scaffolds was synthesized and used to probe selective activation by cells expressing CYP1A1 and 2W1, CYPs known to be expressed in high frequency in some tumors. Several CPI-based compounds were pM-nM potent in CYP1A1 expressing cells. CYP2W1 was also shown to sensitize proliferating cells to several compounds, demonstrating its potential as a target for tumor selective activation of duocarmycin bioprecursors.
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Bradford BD7 1DP, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Sheldrake
authors.forename: Sandra
authors.initials: S
authors.lastname: Travica
authors.forename: Inger
authors.initials: I
authors.lastname: Johansson
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Mark
authors.initials: M
authors.lastname: Sutherland
authors.forename: Lina
authors.initials: L
authors.lastname: Elsalem
authors.forename: Nicola
authors.initials: N
authors.lastname: Illingworth
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Cresswell
authors.forename: Tristan
authors.initials: T
authors.lastname: Reuillon
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Souren
authors.initials: S
authors.lastname: Mkrtchian
authors.forename: Mark
authors.initials: M
authors.lastname: Searcey
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D054852:Small Molecule Libraries; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C509336:CYP2W1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000072467:Cytochrome P450 Family 2