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

D. Vijay Kumar, Christophe Hoarau, Matthew Bursavich, Paul Slattum, David Gerrish, Kraig Yager, Michael Saunders, Mark Shenderovich, Bruce L. Roth, Rena McKinnon, Ashley Chan, Daniel M. Cimbora, Chad Bradford, Leslie Reeves, Scott Patton, Damon I. Papac, Brandi L. Williams, Robert O. Carlson

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23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4377-4385
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Kumar, D. V., Hoarau, C., Bursavich, M., Slattum, P., Gerrish, D., Yager, K., Saunders, M., Shenderovich, M., Roth, B. L., McKinnon, R., Chan, A., Cimbora, D. M., Bradford, C., Reeves, L., Patton, S., Papac, D. I., Williams, B. L., & Carlson, R. O. (2012). Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors. Bioorganic and Medicinal Chemistry Letters, 22(13), 4377-4385. https://doi.org/10.1016/j.bmcl.2012.04.131