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

  • Bioorg Med Chem Lett. 2012 Jul 1;22(13):4377-85. doi: 10.1016/j.bmcl.2012.04.131.
D Vijay Kumar  1 ,  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
Affiliations
  • 1. Department of Medicinal Chemistry, Myrexis Inc., 305 Chipeta Way, Salt Lake City, UT 84108, USA. [email protected]
PMID: 22632936 DOI: 10.1016/j.bmcl.2012.04.131
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.