Abstract
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular d-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.
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Acknowledgements
We thank Ulrike Hars, Ingo P. Korndoerfer and Ismail Moarefi from Crelux GmbH for excellent structural biology support, Antje Habel and Viktoria Zeller for histological expertise, Dr. Tim Holland-Letz for biostatistics support and Dr. Ruth Wellenreuther for valuable administrative support.
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This work was jointly funded by DKFZ and Bayer within their strategic collaboration. Viktoria Fischer is funded by the Bundesministerium für Bildung und Forschung (BMBF; Grant number 031A425A).
Conflict of interest
Stefan Pusch, Jörg Balß and Andreas von Deimling are patent holders of “Means and methods for the determination of (d)-2-hydroxyglutarate (D2HG)”, the enzymatic 2-HG assay used for 2-HG determination in this manuscript (WO2013127997A1). David Capper, Wolfgang Wick and Andreas von Deimling are patent holders of “Methods for the diagnosis and the prognosis of a brain tumor”, the IDH1R132H-specific antibody used in this manuscript (US 8367347 B2). Both patents are under the administrative supervision of the DKFZ technology transfer office. Stefan Kaulfuss, Olaf Panknin, Hartmut Rehwinkel, Katja Zimmermann, Roman C. Hillig, Judith Guenther, Luisella Toschi, Roland Neuhaus, Andrea Haegebart, Holger Hess-Stumpp and Markus Bauser are full-time employees of Bayer Pharma AG and stockholders of Bayer AG share. All other authors declare no potential conflicts of interest.
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Pusch, S., Krausert, S., Fischer, V. et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol 133, 629–644 (2017). https://doi.org/10.1007/s00401-017-1677-y
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DOI: https://doi.org/10.1007/s00401-017-1677-y