Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (13), p.4377-4385
Main Authors: Vijay Kumar, D., Hoarau, Christophe, Bursavich, Matthew, Slattum, Paul, Gerrish, David, Yager, Kraig, Saunders, Michael, Shenderovich, Mark, Roth, Bruce L., McKinnon, Rena, Chan, Ashley, Cimbora, Daniel M., Bradford, Chad, Reeves, Leslie, Patton, Scott, Papac, Damon I., Williams, Brandi L., Carlson, Robert O.
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - chemistry
Adenine - pharmacokinetics
Adenine - toxicity
Administration, Oral
Animals
Apoptosis - drug effects
Binding Sites
bioavailability
Biological and medical sciences
Cancer
chemistry
Crystallography, X-Ray
Cytotoxicity
G2 Phase Cell Cycle Checkpoints - drug effects
HCT116 Cells
Humans
interphase
Kinase selectivity
Lead
Lead optimization
M Phase Cell Cycle Checkpoints - drug effects
Medical sciences
Mice
Molecular Conformation
Morpholines - chemistry
Morpholines - pharmacokinetics
Morpholines - toxicity
Mps1 kinase
Novelty
Pharmacology. Drug treatments
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - toxicity
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - metabolism
purines
Purines - chemistry
Structure-Activity Relationship
TTK kinase
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Summary:Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.04.131