Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

Erik de Heuvel; Abhimanyu K. Singh; Ewald Edink; Tiffany van der Meer; Melanie van der Woude; Payman Sadek; Mikkel P. Krell-Jørgensen; Toine van den Bergh; Johan Veerman; Guy Caljon; Titilola D. Kalejaiye; Maikel Wijtmans; Louis Maes; Harry P. de Koning; Geert Jan Sterk; Marco Siderius; Iwan J.P. de Esch; David G. Brown; Rob Leurs

doi:10.1016/j.bmc.2019.06.027

Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

Erik de Heuvel, Abhimanyu K. Singh, Ewald Edink, Tiffany van der Meer, Melanie van der Woude, Payman Sadek, Mikkel P. Krell-Jørgensen, Toine van den Bergh, Johan Veerman, Guy Caljon, Titilola D. Kalejaiye, Maikel Wijtmans, Louis Maes, Harry P. de Koning, Geert Jan Sterk, Marco Siderius, Iwan J.P. de Esch, David G. Brown, Rob Leurs^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

Original language	English
Pages (from-to)	3998-4012
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	27
Issue number	18
Early online date	18 Jun 2019
DOIs	https://doi.org/10.1016/j.bmc.2019.06.027
Publication status	Published - 15 Sept 2019

Funding

We thank F.G.J. Custers (Vrije Universiteit Amsterdam) for analytical support. We thank Jay Bangs (University at Buffalo) for providing T. brucei brucei culture medium, Viacheslav O. Nikolaev (Universitätsklinikum Hamburg-Eppendorf) for providing the Epac1camps plasmid, Tom Seebeck for the anti-PFR antibody. Funding: This work was supported by the European Commission 7th Framework Programme FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD) and by the European Union’s Horizon2020 MSCA Programme under grant agreement 675899 (FRAGNET). This work was supported in part by grant R01GM109984 to NCS .

Funders	Funder number
Seventh Framework Programme	602666

Keywords

Crystal structure
Human African trypanosomiasis
Neglected tropical disease
Structure-based drug discovery
Tetrahydrophthalazinone
Trypanosoma brucei phosphodiesterase B1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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de Heuvel, E., Singh, A. K., Edink, E., van der Meer, T., van der Woude, M., Sadek, P., Krell-Jørgensen, M. P., van den Bergh, T., Veerman, J., Caljon, G., Kalejaiye, T. D., Wijtmans, M., Maes, L., de Koning, H. P., Jan Sterk, G., Siderius, M., de Esch, I. J. P., Brown, D. G., & Leurs, R. (2019). Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors. Bioorganic and Medicinal Chemistry, 27(18), 3998-4012. https://doi.org/10.1016/j.bmc.2019.06.027

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abstract = "Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.",

keywords = "Crystal structure, Human African trypanosomiasis, Neglected tropical disease, Structure-based drug discovery, Tetrahydrophthalazinone, Trypanosoma brucei phosphodiesterase B1",

author = "{de Heuvel}, Erik and Singh, {Abhimanyu K.} and Ewald Edink and {van der Meer}, Tiffany and {van der Woude}, Melanie and Payman Sadek and Krell-J{\o}rgensen, {Mikkel P.} and {van den Bergh}, Toine and Johan Veerman and Guy Caljon and Kalejaiye, {Titilola D.} and Maikel Wijtmans and Louis Maes and {de Koning}, {Harry P.} and {Jan Sterk}, Geert and Marco Siderius and {de Esch}, {Iwan J.P.} and Brown, {David G.} and Rob Leurs",

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doi = "10.1016/j.bmc.2019.06.027",

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de Heuvel, E, Singh, AK, Edink, E, van der Meer, T, van der Woude, M, Sadek, P, Krell-Jørgensen, MP, van den Bergh, T, Veerman, J, Caljon, G, Kalejaiye, TD, Wijtmans, M, Maes, L, de Koning, HP, Jan Sterk, G, Siderius, M , de Esch, IJP, Brown, DG & Leurs, R 2019, 'Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors', Bioorganic and Medicinal Chemistry, vol. 27, no. 18, pp. 3998-4012. https://doi.org/10.1016/j.bmc.2019.06.027

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AU - de Heuvel, Erik

AU - Singh, Abhimanyu K.

AU - Edink, Ewald

AU - van der Meer, Tiffany

AU - van der Woude, Melanie

AU - Sadek, Payman

AU - Krell-Jørgensen, Mikkel P.

AU - van den Bergh, Toine

AU - Veerman, Johan

AU - Caljon, Guy

AU - Kalejaiye, Titilola D.

AU - Wijtmans, Maikel

AU - Maes, Louis

AU - de Koning, Harry P.

AU - Jan Sterk, Geert

AU - Siderius, Marco

AU - de Esch, Iwan J.P.

AU - Brown, David G.

AU - Leurs, Rob

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

AB - Several 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) have been validated as good drug targets for a large variety of diseases. Trypanosoma brucei PDEB1 (TbrPDEB1) has been designated as a promising drug target for the treatment of human African trypanosomiasis. Recently, the first class of selective nanomolar TbrPDEB1 inhibitors was obtained by targeting the parasite specific P-pocket. However, these biphenyl-substituted tetrahydrophthalazinone-based inhibitors did not show potent cellular activity against Trypanosoma brucei (T. brucei) parasites, leaving room for further optimization. Herein, we report the discovery of a new class of potent TbrPDEB1 inhibitors that display improved activities against T. brucei parasites. Exploring different linkers between the reported tetrahydrophthalazinone core scaffold and the amide tail group resulted in the discovery of alkynamide phthalazinones as new TbrPDEB1 inhibitors, which exhibit submicromolar activities versus T. brucei parasites and no cytotoxicity to human MRC-5 cells. Elucidation of the crystal structure of alkynamide 8b (NPD-048) bound to the catalytic domain of TbrPDEB1 shows a bidentate interaction with the key-residue Gln874 and good directionality towards the P-pocket. Incubation of trypanosomes with alkynamide 8b results in an increase of intracellular cAMP, validating a PDE-mediated effect in vitro and providing a new interesting compound series for further studies towards selective TbrPDEB1 inhibitors with potent phenotypic activity.

KW - Crystal structure

KW - Human African trypanosomiasis

KW - Neglected tropical disease

KW - Structure-based drug discovery

KW - Tetrahydrophthalazinone

KW - Trypanosoma brucei phosphodiesterase B1

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Alkynamide phthalazinones as a new class of TbrPDEB1 inhibitors

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Keywords

UN SDGs

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