Final results of ProGem1, the first in-human phase I/II study of NUC-1031 in patients with solid malignancies.

Blagden, Sarah P.; Rizzuto, Ivana; Stavraka, Chara; O’Shea, Derville; Suppiah, Puvan; Patel, Mohit; Sukumaran, Ajithkumar; Loyse, Naomi; Bharwani, Nishat; Rockall, Andrea; Gabra, Hani; El‐Bahrawy, Mona; Wasan, Harpreet; Leonard, Robert; Habib, Nagy; Gribben, John G.; Ghazaly, Essam; McGuigan, Christopher

doi:10.1200/jco.2015.33.15_suppl.2514

Cited by 7 publications

(11 citation statements)

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“…28 Generally, the prodrug was well-tolerated by patients with the most common adverse effects being anaemia (67%), fatigue (67%), transaminitis (64%) and thrombocytopaenia (53%). 28 Figure 4), 29 showed excellent preclinical properties. 29 McGuigan and co-workers reported the discovery of 6 in 2011 and highlighted its advantageous properties as compared to the parent nucleoside FdU.…”

Section: Phosphoramidate (Protide) Prodrugsmentioning

confidence: 96%

“…27 Results from phase I/II clinical trials showed that 5 was effective against a wide range of cancers that included pancreatic, biliary and ovarian. 28 ProTide 5 achieved ca. 12-fold higher levels of the active metabolite gemcitabine triphosphate than gemcitabine in patients similar to the levels seen in previous animal studies.…”

Section: Phosphoramidate (Protide) Prodrugsmentioning

confidence: 99%

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Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

et al. 2016

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Nucleoside monophosphates and monophosphonates have been known for a long time to exert favorable pharmacological effects upon intracellular delivery. However, their development as drug molecules has been hindered by the inherent poor druglike properties of the monophosphate and monophosphonate groups. These include inefficient cellular uptake and poor in vivo stability, with this latter drawback being most relevant to monophosphates than monophosphonates. To address these limitations, numerous monophosphate and monophosphonate prodrug strategies have been developed and applied in the discovery of nucleoside monophosphate and monophosphonate prodrugs that can treat viral infections and cancer. The approval of sofosbuvir, a nucleoside monophosphate prodrug, highlighted the success to be had by employing these prodrug technologies in the discovery of nucleotide therapeutics. In this Miniperspective, we discuss the different key monophosphate and monophosphonate nucleoside prodrugs that entered clinical development, some of which may in the future be approved to treat various human diseases.

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Section: Phosphoramidate (Protide) Prodrugsmentioning

confidence: 96%

Section: Phosphoramidate (Protide) Prodrugsmentioning

confidence: 99%

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

et al. 2016

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“…stampidine 24 (phase I for HIV treatment, 13), and anticancer (i.e. thymectacin) 25 (phase I/II, 14), NUC-1031 26 (phase II, 15) and NUC-3373 27 (phase I, 16) activity. In our laboratory we have extensively investigated and applied the ProTide technology to a number of antiviral [28][29][30] and anticancer agents such as for example 5-fluoro-2'deoxyuridine (FdUrd), 31 and gemcitabine.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a new class of 2'-fluoro-6-substituted uridine derivatives reported in the literature 7 as potential inhibitors of ODCase revealed the lack of cellular anticancer activities most likely due to their poor activation to the corresponding 5'-monophosphate forms. Herein, we report the ProTide technology approach employed to 6-substituted-5-fluorouridine analogues (5)(6)(7)(8) to design novel nucleoside phosphoramidates (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37) as potential anticancer agents. These compounds were prepared with the aim to improve cellular uptake of their parent nucleoside analogues and intracellular delivery of their corresponding monophosphate forms.…”

Section: Introductionmentioning

confidence: 99%

“…Four classes of 6-substituted-5-fluorouridine target ProTides(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).BiologyThe cytostatic activities of 6-substitited-FUR ProTides 25-37 (Figure 4) were evaluated against various cancer cell lines including human breast adenocarcinoma (MCF-7), colon (SW620), pancreatic (Mia-Pa-Ca), acute myeloid leukaemia (MV4-11), erythroleukaemia (HEL92.1.7), non-Hodgkin's lymphoma (RL) and Hodgkin's lymphoma (HS445). The L-alanine-Bn-Naph 6-I-FUR prodrug 27 was among the most active in the series of all 6-modified-FUR ProTides with submicromolar IC50 values ranging between 0.08 M (MV4-11) and 3.9 M in (MCF-7) cell cultures.…”

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confidence: 99%

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Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides

Ślusarczyk

Ferla

Brancale

et al. 2018

Bioorganic & Medicinal Chemistry

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A new family of thirteen phosphoramidate prodrugs (ProTides) of different 6-substituted-5-fluorouridine nucleoside analogues were synthesized and evaluated as potential anticancer agents. In addition, antiviral activity against Chikungunya (CHIKV) virus was evaluated using a cytopathic effect inhibition assay. Although a carboxypeptidase Y assay supported a putative mechanism of activation of ProTides built on 5-fluorouridine with such C6-modifications, the Hint docking studies revealed a compromised substrate-activity for the Hint phosphoramidase-type enzyme that is likely responsible for phosphoramidate bioactivation through P-N bond cleavage and free nucleoside 5'-monophosphate delivery. Our observations may support and explain to some extent the poor in vitro biological activity generally demonstrated by the series of 6-substituted-5-fluorouridine phosphoramidates (ProTides) and will be of guidance for the design of novel phosphoramidate prodrugs.

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Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5′‐Monophosphate Forms of Anticancer Nucleoside Analogues

et al. 2018

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The application of phosphorodiamidate technology to pyrimidine and purine nucleosides with anticancer activity to potentially overcome the resistance mechanisms associated with parent nucleosides is reported. Sixteen symmetrical phosphorodiamidates were prepared from the natural amino acids l-alanine and glycine. All the compounds were evaluated for their cytotoxic activity against a wide panel of solid and leukaemic tumour cell lines. In addition, a carboxypeptidase Y assay was performed on a representative phosphorodiamidate in order to reveal the putative bioactivation pathway for the reported phosphorodiamidate-type prodrugs.

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Final results of ProGem1, the first in-human phase I/II study of NUC-1031 in patients with solid malignancies.

Cited by 7 publications

References 0 publications

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

Nucleoside Phosphate and Phosphonate Prodrug Clinical Candidates

Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides

Symmetrical Diamidates as a Class of Phosphate Prodrugs to Deliver the 5′‐Monophosphate Forms of Anticancer Nucleoside Analogues

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