title: BI 885578, a Novel IGF1R/INSR Tyrosine Kinase Inhibitor with Pharmacokinetic Properties That Dissociate Antitumor Efficacy and Perturbation of Glucose Homeostasis.
abstract: Inhibition of the IGF1R, INSRA, and INSRB receptor tyrosine kinases represents an attractive approach of pharmacologic intervention in cancer, owing to the roles of the IGF1R and INSRA in promoting cell proliferation and survival. However, the central role of the INSRB isoform in glucose homeostasis suggests that prolonged inhibition of this kinase could result in metabolic toxicity. We describe here the profile of the novel compound BI 885578, a potent and selective ATP-competitive IGF1R/INSR tyrosine kinase inhibitor distinguished by rapid intestinal absorption and a short in vivo half-life as a result of rapid metabolic clearance. BI 885578, administered daily per os, displayed an acceptable tolerability profile in mice at doses that significantly reduced the growth of xenografted human GEO and CL-14 colon carcinoma tumors. We found that treatment with BI 885578 is accompanied by increases in circulating glucose and insulin levels, which in turn leads to compensatory hyperphosphorylation of muscle INSRs and subsequent normalization of blood glucose within a few hours. In contrast, the normalization of IGF1R and INSR phosphorylation in GEO tumors occurs at a much slower rate. In accordance with this, BI 885578 led to a prolonged inhibition of cell proliferation and induction of apoptosis in GEO tumors. We propose that the remarkable therapeutic window observed for BI 885578 is achieved by virtue of the distinctive pharmacokinetic properties of the compound, capitalizing on the physiologic mechanisms of glucose homeostasis and differential levels of IGF1R and INSR expression in tumors and normal tissues.
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria. michael.sanderson@boehringer-ingelheim.com.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Sanderson
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Joshua
authors.initials: J
authors.lastname: Apgar
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garin-Chesa
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Marco H
authors.initials: MH
authors.lastname: Hofmann
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Kessler
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Jens
authors.initials: J
authors.lastname: Quant
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Savchenko
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Otmar
authors.initials: O
authors.lastname: Schaaf
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Treu
authors.affiliation: Evotec (UK) Ltd., Abingdon, Oxfordshire, United Kingdom.
authors.forename: Heather
authors.initials: H
authors.lastname: Tye
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Stephan K
authors.initials: SK
authors.lastname: Zahn
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zoephel
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Eric
authors.initials: E
authors.lastname: Haaksma
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Günther R
authors.initials: GR
authors.lastname: Adolf
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co KG, Department of Pharmacology, Dr. Boehringer-Gasse, Vienna, Austria.
authors.forename: Norbert
authors.initials: N
authors.lastname: Kraut
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; C000610673:BI 885578; C000597236:IGF1R protein, human; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D017451:Receptors, Somatomedin; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose