title: CH-01 is a hypoxia-activated prodrug that sensitizes cells to hypoxia/reoxygenation through inhibition of Chk1 and Aurora A.
abstract: The increased resistance of hypoxic cells to all forms of cancer therapy presents a major barrier to the successful treatment of most solid tumors. Inhibition of the essential kinase Checkpoint kinase 1 (Chk1) has been described as a promising cancer therapy for tumors with high levels of hypoxia-induced replication stress. However, as inhibition of Chk1 affects normal replication and induces DNA damage, these agents also have the potential to induce genomic instability and contribute to tumorigenesis. To overcome this problem, we have developed a bioreductive prodrug, which functions as a Chk1/Aurora A inhibitor specifically in hypoxic conditions. To achieve this activity, a key functionality on the Chk1 inhibitor (CH-01) is masked by a bioreductive group, rendering the compound inactive as a Chk1/Aurora A inhibitor. Reduction of the bioreductive group nitro moiety, under hypoxic conditions, reveals an electron-donating substituent that leads to fragmentation of the molecule, affording the active inhibitor. Most importantly, we show a significant loss of viability in cancer cell lines exposed to hypoxia in the presence of CH-01. This novel approach targets the most aggressive and therapy-resistant tumor fraction while protecting normal tissue from therapy-induced genomic instability.
authors.affiliation: Cancer Research U.K./MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford , Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
authors.forename: Cindy
authors.initials: C
authors.lastname: Cazares-Körner
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Pires
authors.forename: I Diane
authors.initials: ID
authors.lastname: Swallow
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Grayer
authors.forename: Liam J
authors.initials: LJ
authors.lastname: O'Connor
authors.forename: Monica M
authors.initials: MM
authors.lastname: Olcina
authors.forename: Martin
authors.initials: M
authors.lastname: Christlieb
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D010084:Oxidation-Reduction / Q000187:drug effects; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000592894:CH-01 compound; D004791:Enzyme Inhibitors; D005663:Furans; D011355:Prodrugs; D011743:Pyrimidines; D011494:Protein Kinases; D064096:Aurora Kinase A; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1