title: Modeling bone marrow toxicity using kinase structural motifs and the inhibition profiles of small molecular kinase inhibitors.
abstract: The cellular function of kinases combined with the difficulty of designing selective small molecule kinase inhibitors (SMKIs) poses a challenge for drug development. The late-stage attrition of SMKIs could be lessened by integrating safety information of kinases into the lead optimization stage of drug development. Herein, a mathematical model to predict bone marrow toxicity (BMT) is presented which enables the rational design of SMKIs away from this safety liability. A specific example highlights how this model identifies critical structural modifications to avoid BMT. The model was built using a novel algorithm, which selects 19 representative kinases from a panel of 277 based upon their ATP-binding pocket sequences and ability to predict BMT in vivo for 48 SMKIs. A support vector machine classifier was trained on the selected kinases and accurately predicts BMT with 74% accuracy. The model provides an efficient method for understanding SMKI-induced in vivo BMT earlier in drug discovery.
authors.affiliation: Non-Clinical Safety, Hoffmann-La Roche, Nutley, New Jersey 07110, USA. andrew.olaharski@roche.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olaharski
authors.forename: Hans
authors.initials: H
authors.lastname: Bitter
authors.forename: Nina
authors.initials: N
authors.lastname: Gonzaludo
authors.forename: Rama
authors.initials: R
authors.lastname: Kondru
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.forename: Tanja S
authors.initials: TS
authors.lastname: Zabka
authors.forename: Henry
authors.initials: H
authors.lastname: Lin
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Kyle
authors.initials: K
authors.lastname: Kolaja
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001185:Artificial Intelligence; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000201:enzymology; D019295:Computational Biology; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012372:ROC Curve
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases