Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

Annelot C M van Esbroeck; Antonius P A Janssen; Armand B Cognetta; Daisuke Ogasawara; Guy Shpak; Mark van der Kroeg; Vasudev Kantae; Marc P Baggelaar; Femke M S de Vrij; Hui Deng; Marco Allarà; Filomena Fezza; Zhanmin Lin; Tom van der Wel; Marjolein Soethoudt; Elliot D Mock; Hans den Dulk; Ilse L Baak; Bogdan I Florea; Giel Hendriks; Luciano De Petrocellis; Herman S Overkleeft; Thomas Hankemeier; Chris I De Zeeuw; Vincenzo Di Marzo; Mauro Maccarrone; Benjamin F Cravatt; Steven A Kushner; Mario van der Stelt

doi:10.1126/science.aaf7497

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

Annelot C M van Esbroeck, Antonius P A Janssen, Armand B Cognetta, Daisuke Ogasawara, Guy Shpak, Mark van der Kroeg, Vasudev Kantae, Marc P Baggelaar, Femke M S de Vrij, Hui Deng, Marco Allarà, Filomena Fezza, Zhanmin Lin, Tom van der Wel, Marjolein Soethoudt, Elliot D Mock, Hans den Dulk, Ilse L Baak, Bogdan I Florea, Giel HendriksLuciano De Petrocellis, Herman S Overkleeft, Thomas Hankemeier, Chris I De Zeeuw, Vincenzo Di Marzo, Mauro Maccarrone, Benjamin F Cravatt, Steven A Kushner, Mario van der Stelt

Netherlands Institute for Neuroscience (NIN)

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

257 Citations (Scopus)

Abstract

A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

Original language	English
Pages (from-to)	1084-1087
Number of pages	4
Journal	Science
Volume	356
Issue number	6342
DOIs	https://doi.org/10.1126/science.aaf7497
Publication status	Published - 01 Jun 2017

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van Esbroeck, A. C. M., Janssen, A. P. A., Cognetta, A. B., Ogasawara, D., Shpak, G., van der Kroeg, M., Kantae, V., Baggelaar, M. P., de Vrij, F. M. S., Deng, H., Allarà, M., Fezza, F., Lin, Z., van der Wel, T., Soethoudt, M., Mock, E. D., den Dulk, H., Baak, I. L., Florea, B. I., ... van der Stelt, M. (2017). Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science, 356(6342), 1084-1087. https://doi.org/10.1126/science.aaf7497

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title = "Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474",

abstract = "A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.",

keywords = "Journal Article",

author = "{van Esbroeck}, {Annelot C M} and Janssen, {Antonius P A} and Cognetta, {Armand B} and Daisuke Ogasawara and Guy Shpak and {van der Kroeg}, Mark and Vasudev Kantae and Baggelaar, {Marc P} and {de Vrij}, {Femke M S} and Hui Deng and Marco Allar{\`a} and Filomena Fezza and Zhanmin Lin and {van der Wel}, Tom and Marjolein Soethoudt and Mock, {Elliot D} and {den Dulk}, Hans and Baak, {Ilse L} and Florea, {Bogdan I} and Giel Hendriks and {De Petrocellis}, Luciano and Overkleeft, {Herman S} and Thomas Hankemeier and {De Zeeuw}, {Chris I} and {Di Marzo}, Vincenzo and Mauro Maccarrone and Cravatt, {Benjamin F} and Kushner, {Steven A} and {van der Stelt}, Mario",

note = "Copyright {\textcopyright} 2017, American Association for the Advancement of Science.",

year = "2017",

month = jun,

day = "1",

doi = "10.1126/science.aaf7497",

language = "English",

volume = "356",

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journal = "Science",

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van Esbroeck, ACM, Janssen, APA, Cognetta, AB, Ogasawara, D, Shpak, G, van der Kroeg, M, Kantae, V, Baggelaar, MP, de Vrij, FMS, Deng, H, Allarà, M, Fezza, F, Lin, Z, van der Wel, T, Soethoudt, M, Mock, ED, den Dulk, H, Baak, IL, Florea, BI, Hendriks, G, De Petrocellis, L, Overkleeft, HS, Hankemeier, T, De Zeeuw, CI, Di Marzo, V, Maccarrone, M, Cravatt, BF, Kushner, SA & van der Stelt, M 2017, 'Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474', Science, vol. 356, no. 6342, pp. 1084-1087. https://doi.org/10.1126/science.aaf7497

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T1 - Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

AU - van Esbroeck, Annelot C M

AU - Janssen, Antonius P A

AU - Cognetta, Armand B

AU - Ogasawara, Daisuke

AU - Shpak, Guy

AU - van der Kroeg, Mark

AU - Kantae, Vasudev

AU - Baggelaar, Marc P

AU - de Vrij, Femke M S

AU - Deng, Hui

AU - Allarà, Marco

AU - Fezza, Filomena

AU - Lin, Zhanmin

AU - van der Wel, Tom

AU - Soethoudt, Marjolein

AU - Mock, Elliot D

AU - den Dulk, Hans

AU - Baak, Ilse L

AU - Florea, Bogdan I

AU - Hendriks, Giel

AU - De Petrocellis, Luciano

AU - Overkleeft, Herman S

AU - Hankemeier, Thomas

AU - De Zeeuw, Chris I

AU - Di Marzo, Vincenzo

AU - Maccarrone, Mauro

AU - Cravatt, Benjamin F

AU - Kushner, Steven A

AU - van der Stelt, Mario

PY - 2017/6/1

Y1 - 2017/6/1

N2 - A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

AB - A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.

KW - Journal Article

U2 - 10.1126/science.aaf7497

DO - 10.1126/science.aaf7497

M3 - Article

C2 - 28596366

SN - 0036-8075

VL - 356

SP - 1084

EP - 1087

JO - Science

JF - Science

IS - 6342

ER -

Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

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