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Article ; Online: Spin Trapping Hydroxyl and Aryl Radicals of One-Electron Reduced Anticancer Benzotriazine 1,4-Dioxides.

Qi, Wen / Yadav, Pooja / Hong, Cho R / Stevenson, Ralph J / Hay, Michael P / Anderson, Robert F

2022 Volume 27, Issue 3

Abstract: Hypoxia in tumors results in resistance to both chemotherapy and radiotherapy treatments but affords an environment in which hypoxia-activated prodrugs (HAP) are activated upon bioreduction to release targeted cytotoxins. The benzotriazine 1,4-di- ...

Abstract	Hypoxia in tumors results in resistance to both chemotherapy and radiotherapy treatments but affords an environment in which hypoxia-activated prodrugs (HAP) are activated upon bioreduction to release targeted cytotoxins. The benzotriazine 1,4-di-
MeSH term(s)	Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Survival/drug effects ; Electrons ; Free Radicals/chemistry ; HCT116 Cells ; HT29 Cells ; Humans ; Hydroxyl Radical/chemistry ; Neoplasms/drug therapy ; Spin Trapping ; Triazines/chemistry ; Triazines/pharmacology
Chemical Substances	Antineoplastic Agents ; Free Radicals ; Triazines ; Hydroxyl Radical (3352-57-6)
Language	English
Publishing date	2022-01-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27030812
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Article ; Online: Design, Synthesis and Anticancer Evaluation of Nitroimidazole Radiosensitisers.

Liew, Lydia P / Shome, Avik / Wong, Way W / Hong, Cho R / Hicks, Kevin O / Jamieson, Stephen M F / Hay, Michael P

Molecules (Basel, Switzerland)

2023 Volume 28, Issue 11

Abstract: The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy ... ...

Abstract	The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.
MeSH term(s)	Humans ; Cell Hypoxia ; Nitroimidazoles/pharmacology ; Radiation-Sensitizing Agents/pharmacology ; Hypoxia ; Neoplasms/drug therapy ; Neoplasms/radiotherapy
Chemical Substances	Nitroimidazoles ; Radiation-Sensitizing Agents
Language	English
Publishing date	2023-05-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules28114457
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Article ; Online: Hypoxia-activated prodrugs of phenolic olaparib analogues for tumour-selective chemosensitisation.

Wong, Way W / O'Brien-Gortner, Sophia F / Anderson, Robert F / Wilson, William R / Hay, Michael P / Dickson, Benjamin D

RSC medicinal chemistry

2023 Volume 14, Issue 7, Page(s) 1309–1330

Abstract: Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal ... ...

Abstract	Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal tissue toxicity. Development of hypoxia-activated prodrugs (HAPs) of PARPi has potential to restrict PARP inhibition to tumours thereby avoiding off-target toxicity. We have designed and synthesised phenolic derivatives of olaparib (termed phenolaparibs) and corresponding ether-linked HAPs. Phenolaparib cytotoxicity in HR-proficient and deficient cell lines was consistent with inhibition of PARP-1. Prodrugs were deactivated relative to phenolaparibs in biochemical PARP-1 inhibition assays, and cell culture. Prodrug 7 was selectively converted to phenolaparib 4 under hypoxia and demonstrated hypoxia-selective cytotoxicity, including chemosensitisation of HR-proficient cells in combination with temozolomide. This work demonstrates the feasibility of a HAP approach to PARPi for use in combination therapies.
Language	English
Publishing date	2023-06-08
Publishing country	England
Document type	Journal Article
ISSN	2632-8682
ISSN (online)	2632-8682
DOI	10.1039/d3md00117b
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Article ; Online: Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors.

Dickson, Benjamin D / Wong, Way Wua / Wilson, William R / Hay, Michael P

Molecules (Basel, Switzerland)

2019 Volume 24, Issue 8

Abstract: Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR ... ...

Abstract	Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity. We have investigated potential HAPs of model PARPi in which we attach a bioreducible "trigger" to the amide nitrogen, thereby blocking key binding interactions. A representative example showed promise in abrogating PARPi enzymatic activity in a biochemical assay, with a ca. 160-fold higher potency of benzyl phthalazinone
MeSH term(s)	Antineoplastic Agents/chemistry ; Chromatography, Liquid ; Magnetic Resonance Spectroscopy ; Mass Spectrometry ; Poly(ADP-ribose) Polymerase Inhibitors/chemistry ; Prodrugs/chemistry ; Quinazolines/chemistry
Chemical Substances	Antineoplastic Agents ; NU 1025 ; Poly(ADP-ribose) Polymerase Inhibitors ; Prodrugs ; Quinazolines
Language	English
Publishing date	2019-04-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules24081559
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Article ; Online: Targeting growth hormone function: strategies and therapeutic applications.

Lu, Man / Flanagan, Jack U / Langley, Ries J / Hay, Michael P / Perry, Jo K

Signal transduction and targeted therapy

2019 Volume 4, Page(s) 3

Abstract: Human growth hormone (GH) is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems. GH is also expressed in extrapituitary tissues and has localized ... ...

Abstract	Human growth hormone (GH) is a classical pituitary endocrine hormone that is essential for normal postnatal growth and has pleiotropic effects across multiple physiological systems. GH is also expressed in extrapituitary tissues and has localized autocrine/paracrine effects at these sites. In adults, hypersecretion of GH causes acromegaly, and strategies that block the release of GH or that inhibit GH receptor (GHR) activation are the primary forms of medical therapy for this disease. Overproduction of GH has also been linked to cancer and the microvascular complications that are associated with diabetes. However, studies to investigate the therapeutic potential of GHR antagonism in these diseases have been limited, most likely due to difficulty in accessing therapeutic tools to study the pharmacology of the receptor in vivo. This review will discuss current and emerging strategies for antagonizing GH function and the potential disease indications.
Language	English
Publishing date	2019-02-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2886872-9
ISSN	2059-3635 ; 2095-9907
ISSN (online)	2059-3635
ISSN	2095-9907
DOI	10.1038/s41392-019-0036-y
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Article ; Online: Targeting hypoxia in cancer therapy.

Wilson, William R / Hay, Michael P

Nature reviews. Cancer

2011 Volume 11, Issue 6, Page(s) 393–410

Abstract: Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, ... ...

Abstract	Hypoxia is a feature of most tumours, albeit with variable incidence and severity within a given patient population. It is a negative prognostic and predictive factor owing to its multiple contributions to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, resistance to cell death, altered metabolism and genomic instability. Given its central role in tumour progression and resistance to therapy, tumour hypoxia might well be considered the best validated target that has yet to be exploited in oncology. However, despite an explosion of information on hypoxia, there are still major questions to be addressed if the long-standing goal of exploiting tumour hypoxia is to be realized. Here, we review the two main approaches, namely bioreductive prodrugs and inhibitors of molecular targets upon which hypoxic cell survival depends. We address the particular challenges and opportunities these overlapping strategies present, and discuss the central importance of emerging diagnostic tools for patient stratification in targeting hypoxia.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Biomarkers, Tumor ; Cell Hypoxia/drug effects ; Humans ; Molecular Targeted Therapy ; Neoplasms/blood supply ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Prodrugs/therapeutic use ; Prognosis ; Reactive Oxygen Species/metabolism
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Prodrugs ; Reactive Oxygen Species
Language	English
Publishing date	2011-05-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/nrc3064
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Article: Efficient Protocol for the Identification of Hypoxic Cell Radiosensitisers.

Hong, Cho Rong / Wang, Jingli / Hicks, Kevin O / Hay, Michael P

Advances in experimental medicine and biology

2016 Volume 899, Page(s) 269–290

Abstract: An evolution in radiotherapy practice is leading to greater use of stereotactic body radiotherapy (SBRT), raising the prospect of increased hypoxic cell radioresistance. New clinical interest in nitroimidazole radiosensitisers, combined with appropriate ... ...

Abstract	An evolution in radiotherapy practice is leading to greater use of stereotactic body radiotherapy (SBRT), raising the prospect of increased hypoxic cell radioresistance. New clinical interest in nitroimidazole radiosensitisers, combined with appropriate biomarkers, signals a revival for radiosensitisers in the context of SBRT. Our interest in modifiers of radiation therapy led us to revisit this area and we have identified a new class of nitroimidazole radiosensitiser. We have developed an abbreviated screening protocol suitable for an academic drug discovery laboratory which allows expeditious triage of compounds with poor physicochemical and in vitro properties and combines in vitro radiosensitisation data with tumour pharmacokinetic data to efficiently select candidates for further evaluation.
MeSH term(s)	Animals ; Biological Transport/drug effects ; Biomarkers/metabolism ; Cell Hypoxia/drug effects ; Female ; HCT116 Cells ; Humans ; Mice, Nude ; Neoplasms/pathology ; Radiation-Sensitizing Agents/analysis ; Radiation-Sensitizing Agents/pharmacokinetics ; Radiation-Sensitizing Agents/pharmacology ; Radiosurgery
Chemical Substances	Biomarkers ; Radiation-Sensitizing Agents
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-319-26666-4_16
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Article: Hypoxia-directed drug strategies to target the tumor microenvironment.

Hay, Michael P / Hicks, Kevin O / Wang, Jingli

Advances in experimental medicine and biology

2014 Volume 772, Page(s) 111–145

Abstract: Hypoxia is an important component of the tumor microenvironment and has been the target of drug discovery efforts for almost half a century. These efforts have evolved from offsetting the impact of hypoxia on radiotherapy with oxygen-mimetic ... ...

Abstract	Hypoxia is an important component of the tumor microenvironment and has been the target of drug discovery efforts for almost half a century. These efforts have evolved from offsetting the impact of hypoxia on radiotherapy with oxygen-mimetic radiosensitizers to using hypoxia as a means to selectively target tumors. The more recent description of hypoxia-inducible factors and their role in the hypoxia response network has revealed a host of new drug targets to selectively target tumors. We are developing hypoxia-directed drugs in each of the following areas: novel radiosensitizers for hypofractionated radiotherapy, a second-generation benzotriazine di-N-oxide hypoxia-activated prodrug, and a hypoxia-inducible factor-1-dependent cytotoxin that targets glucose transport. These projects are discussed in the context of hypoxia-directed drug discovery.
MeSH term(s)	Animals ; Antineoplastic Agents/therapeutic use ; Cell Hypoxia/genetics ; DNA Repair/physiology ; Drug Discovery/methods ; Humans ; Hypoxia-Inducible Factor 1/antagonists & inhibitors ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Radiation-Sensitizing Agents/therapeutic use ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/physiology
Chemical Substances	Antineoplastic Agents ; Hypoxia-Inducible Factor 1 ; Radiation-Sensitizing Agents
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-5915-6_6
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Article ; Online: Hypoxia-Activated Prodrugs of PERK Inhibitors.

Liew, Lydia P / Singleton, Dean C / Wong, Way W / Cheng, Gary J / Jamieson, Stephen M F / Hay, Michael P

Chemistry, an Asian journal

2019 Volume 14, Issue 8, Page(s) 1238–1248

Abstract: Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling ...

Abstract	Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R-like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on-mechanism normal tissue toxicity. Hypoxia presents a target for tumour-selective drug delivery using hypoxia-activated prodrugs. We designed and prepared hypoxia-activated prodrugs of modified PERK inhibitors using a 2-nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2-substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia-selective manner.
MeSH term(s)	Dose-Response Relationship, Drug ; Drug Design ; HCT116 Cells ; Humans ; Hypoxia/metabolism ; Molecular Structure ; Nitroimidazoles/chemical synthesis ; Nitroimidazoles/chemistry ; Nitroimidazoles/metabolism ; Nitroimidazoles/pharmacology ; Prodrugs/chemical synthesis ; Prodrugs/chemistry ; Prodrugs/metabolism ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Structure-Activity Relationship ; Tumor Cells, Cultured ; eIF-2 Kinase/antagonists & inhibitors ; eIF-2 Kinase/metabolism
Chemical Substances	Nitroimidazoles ; Prodrugs ; Protein Kinase Inhibitors ; EIF2AK3 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2019-01-29
Publishing country	Germany
Document type	Journal Article
ISSN	1861-471X
ISSN (online)	1861-471X
DOI	10.1002/asia.201801826
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Article ; Online: Radiosensitization of head and neck squamous cell carcinoma lines by DNA-PK inhibitors is more effective than PARP-1 inhibition and is enhanced by SLFN11 and hypoxia.

Lee, Tet Woo / Wong, Way Wua / Dickson, Benjamin D / Lipert, Barbara / Cheng, Gary J / Hunter, Francis W / Hay, Michael P / Wilson, William R

International journal of radiation biology

2019 Volume 95, Issue 12, Page(s) 1597–1612

Abstract: Background and purpose: ...

Abstract	Background and purpose:
MeSH term(s)	Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Proliferation/radiation effects ; DNA-Activated Protein Kinase/antagonists & inhibitors ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/radiation effects ; Humans ; Nuclear Proteins/metabolism ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Radiation-Sensitizing Agents/pharmacology ; Squamous Cell Carcinoma of Head and Neck/pathology ; Time Factors ; Tumor Hypoxia/drug effects ; Tumor Hypoxia/radiation effects
Chemical Substances	Nuclear Proteins ; Poly(ADP-ribose) Polymerase Inhibitors ; Protein Kinase Inhibitors ; Radiation-Sensitizing Agents ; SLFN11 protein, human ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; DNA-Activated Protein Kinase (EC 2.7.11.1)
Language	English
Publishing date	2019-09-17
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3065-x
ISSN	1362-3095 ; 0020-7616 ; 0955-3002
ISSN (online)	1362-3095
ISSN	0020-7616 ; 0955-3002
DOI	10.1080/09553002.2019.1664787
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