Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506

Wiel, Alexander M.A. van der; Jackson-Patel, Victoria; Niemans, Raymon; Yaromina, Ala; Liu, Emily; Marcus, Damiënne; Mowday, Alexandra M.; Lieuwes, Natasja G.; Biemans, Rianne; Lin, Xiaojing; Fu, Zhe; Kumara, Sisira; Jochems, Arthur; Ashoorzadeh, Amir; Anderson, Robert F.; Hicks, Kevin O.; Bull, Matthew R.; Guise, Christopher P.; Deschoemaeker, Sofie; Thiolloy, Sophie; Heyerick, Arne; Solivio, Morwena J.; Balbo, Silvia; Smaill, Jeff B.; Theys, Jan; Dubois, Ludwig; Patterson, Adam V.

doi:10.1158/1535-7163.mct-21-0406

Cited by 20 publications

(38 citation statements)

References 45 publications

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“…Synthesis of intermediate 17 has been previously described by our group during the preparation of the hypoxia-activated prodrug CP-506 [23] and is briefly included here for completeness. Key intermediates 17-19 were prepared by nucleophilic displacement of the 4-fluoro substituent of commercially available 3,4-difluorobenzaldehyde (10) with the respective sodium alkyl sulfinates to give the alkyl sulfones 11-13, followed by oxidation to afford the carboxylic acids 14-16 and subsequent nitration mediated by fuming nitric acid (Scheme 1).…”

Section: Chemical Synthesismentioning

confidence: 99%

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

et al. 2022

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PR-104A is a dual hypoxia/nitroreductase gene therapy prodrug by virtue of its ability to undergo either one- or two-electron reduction to its cytotoxic species. It has been evaluated extensively in pre-clinical GDEPT studies, yet off-target human aldo-keto reductase AKR1C3-mediated activation has limited its use. Re-evaluation of this chemical scaffold has previously identified SN29176 as an improved hypoxia-activated prodrug analogue of PR-104A that is free from AKR1C3 activation. However, optimization of the bystander effect of SN29176 is required for use in a GDEPT setting to compensate for the non-uniform distribution of therapeutic gene transfer that is often observed with current gene therapy vectors. A lipophilic series of eight analogues were synthesized from commercially available 3,4-difluorobenzaldehyde. Calculated octanol-water partition coefficients (LogD7.4) spanned >2 orders of magnitude. 2D anti-proliferative and 3D multicellular layer assays were performed using isogenic HCT116 cells expressing E. coli NfsA nitroreductase (NfsA_Ec) or AKR1C3 to determine enzyme activity and measure bystander effect. A variation in potency for NfsA_Ec was observed, while all prodrugs appeared AKR1C3-resistant by 2D assay. However, 3D assays indicated that increasing prodrug lipophilicity correlated with increased AKR1C3 activation and NfsA_Ec activity, suggesting that metabolite loss from the cell of origin into media during 2D monolayer assays could mask cytotoxicity. Three prodrugs were identified as bono fide AKR1C3-negative candidates whilst maintaining activity with NfsA_Ec. These were converted to their phosphate ester pre-prodrugs before being taken forward into in vivo therapeutic efficacy studies. Ultimately, 2-(5-(bis(2-bromoethyl)amino)-4-(ethylsulfonyl)-N-methyl-2-nitrobenzamido)ethyl dihydrogen phosphate possessed a significant 156% improvement in median survival in mixed NfsA_Ec/WT tumors compared to untreated controls (p = 0.005), whilst still maintaining hypoxia selectivity comparable to PR-104A.

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Section: Chemical Synthesismentioning

confidence: 99%

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

et al. 2022

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“…The bystander effect results from local diffusion of the active drug metabolites, and is important to overcome unequal delivery of the drug [ 114 ]. These favorable pharmacokinetic properties were confirmed in vitro and in vivo, next to a broad antitumor activity in HNSCC [ 102 ].…”

Section: Hypoxia-targeting Strategiesmentioning

confidence: 93%

“…Based on PR-104, a new and improved HAP was developed: CP-506. The main advantages of this novel agent include AKR1C3 resistance, water-solubility, orally bioavailability, and a large bystander effect [ 102 ]. The bystander effect results from local diffusion of the active drug metabolites, and is important to overcome unequal delivery of the drug [ 114 ].…”

Section: Hypoxia-targeting Strategiesmentioning

confidence: 99%

Hypoxia and Its Influence on Radiotherapy Response of HPV-Positive and HPV-Negative Head and Neck Cancer

Wegge

Dok

Nuyts

2021

Cancers

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Head and neck squamous cancers are a heterogeneous group of cancers that arise from the upper aerodigestive tract. Etiologically, these tumors are linked to alcohol/tobacco abuse and infections with high-risk human papillomavirus (HPV). HPV-positive HNSCCs are characterized by a different biology and also demonstrate better therapy response and survival compared to alcohol/tobacco-related HNSCCs. Despite this advantageous therapy response and the clear biological differences, all locally advanced HNSCCs are treated with the same chemo-radiotherapy schedules. Although we have a better understanding of the biology of both groups of HNSCC, the biological factors associated with the increased radiotherapy response are still unclear. Hypoxia, i.e., low oxygen levels because of an imbalance between oxygen demand and supply, is an important biological factor associated with radiotherapy response and has been linked with HPV infections. In this review, we discuss the effects of hypoxia on radiotherapy response, on the tumor biology, and the tumor microenvironment of HPV-positive and HPV-negative HNSCCs by pointing out the differences between these two tumor types. In addition, we provide an overview of the current strategies to detect and target hypoxia.

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“…This toxicity was later shown [20] to be due to aerobic activation by the aldo-keto reductase (AKR1C3) enzyme, not previously recognised as a nitroreductase. Later development of the class resulted in the related compound CP-506 (9), which did not have this liability and was shown to effectively decrease the hypoxic fraction and inhibit the growth of a wide range of hypoxic xenografted tumours [21]. This compound is currently in Phase II clinical trial [22].…”

Section: Prodrugs Activated By Fragmentationmentioning

confidence: 99%

“…The prodrug was inactive with a minimum inhibitory concentration (MIC) >256 µg/mL in both strains, but when reduced (chemically, by SnCl 2 ) showed MICs of 2-4 µg/mL. Luo et al [29] developed a dual-release drug (21), which simultaneously generated YCH-1 hemisuccinate, which rapidly cyclised to give the HIF-1α expression inhibitor YCH-1 (22) and doxorubicin (23). In human adenocarcinoma A549 cells the prodrug 21 had an IC 50 of 9.6 µM compared with free doxorubicin (IC 50 4.3 µM) but was considerably more cytotoxic (IC 50 1.2 µM) under hypoxia.…”

Section: -Nitrobenzyl Triggersmentioning

confidence: 99%

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

Denny

2022

Pharmaceuticals

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The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. The vast majority of hypoxia-activated fall into the latter category and are discussed here classed by the nature of their nitroaromatic trigger units.

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Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506

Cited by 20 publications

References 45 publications

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

Interrogation of the Structure–Activity Relationship of a Lipophilic Nitroaromatic Prodrug Series Designed for Cancer Gene Therapy Applications

Hypoxia and Its Influence on Radiotherapy Response of HPV-Positive and HPV-Negative Head and Neck Cancer

Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy

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