title: Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
abstract: Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. ©2016 AACR.
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. patrizia.sini@boehringer-ingelheim.com.
authors: Patrizia
authors: P
authors: Sini
authors: Department of R&D Project Management, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors: Ulrich
authors: U
authors: Gürtler
authors: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Stephan K
authors: SK
authors: Zahn
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Christoph
authors: C
authors: Baumann
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Dorothea
authors: D
authors: Rudolph
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Rosa
authors: R
authors: Baumgartinger
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Eva
authors: E
authors: Strauss
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Christian
authors: C
authors: Haslinger
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Ulrike
authors: U
authors: Tontsch-Grunt
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Irene C
authors: IC
authors: Waizenegger
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Flavio
authors: F
authors: Solca
authors: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Gerd
authors: G
authors: Bader
authors: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Andreas
authors: A
authors: Zoephel
authors: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Matthias
authors: M
authors: Treu
authors: Department of Medicinal Chemistry, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Ulrich
authors: U
authors: Reiser
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Pilar
authors: P
authors: Garin-Chesa
authors: Research Networking, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Guido
authors: G
authors: Boehmelt
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Norbert
authors: N
authors: Kraut
authors: Research ADME, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Jens
authors: J
authors: Quant
authors: Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
authors: Günther R
authors: GR
authors: Adolf
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D064127:Aurora Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D064127:Aurora Kinases; D020929:Mitogen-Activated Protein Kinase Kinases