Modeling bone marrow toxicity using kinase structural motifs and the inhibition profiles of small molecular kinase inhibitors.
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.
Olaharski
Andrew J
AJ
Non-Clinical Safety, Hoffmann-La Roche, Nutley, New Jersey 07110, USA. andrew.olaharski@roche.com
Bitter
Hans
H
Gonzaludo
Nina
N
Kondru
Rama
R
Goldstein
David M
DM
Zabka
Tanja S
TS
Lin
Henry
H
Singer
Thomas
T
Kolaja
Kyle
K
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
D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D011494:Protein Kinases