Efficient optimization strategy for marginal hits active against abl tyrosine kinases.
Primary high-throughput screening of commercially available small molecules collections often results in hit compounds with unfavorable ADME/Tox properties and low IP potential. These issues are addressed empirically at follow-up lead development and optimization stages. In this work, we describe a rational approach to the optimization of hit compounds discovered during screening of a kinase focused library against abl tyrosine kinase. The optimization strategy involved application of modern chemoinformatics techniques, such as automatic bioisosteric transformation of the initial hits, efficient solution-phase combinatorial synthesis, and advanced methods of knowledge-based libraries design.
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Sergey E
SE
Tkachenko
Ilya
I
Okun
Konstantin V
KV
Balakin
Charles E
CE
Petersen
Yan A
YA
Ivanenkov
Nikolay P
NP
Savchuk
Andrey A
AA
Ivashchenko
D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D019295:Computational Biology; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016313:Genes, abl / Q000235:genetics*; D008956:Models, Chemical; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases