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

doi:10.1016/j.bmcl.2012.04.131

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

Eberly College of Science

Research output: Contribution to journal › Article › peer-review

33 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 language	English (US)
Pages (from-to)	4377-4385
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2012.04.131
State	Published - 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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10.1016/j.bmcl.2012.04.131

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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

@article{b11ce319628e4cd29e869be2bf4c8d61,

title = "Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors",

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.",

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

year = "2012",

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doi = "10.1016/j.bmcl.2012.04.131",

language = "English (US)",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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Kumar, DV, Hoarau, C, Bursavich, M, Slattum, P, Gerrish, D, Yager, K, Saunders, M, Shenderovich, M, Roth, BL, McKinnon, R, Chan, A, Cimbora, DM, Bradford, C, Reeves, L, Patton, S, Papac, DI, Williams, BL & Carlson, RO 2012, 'Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 13, pp. 4377-4385. https://doi.org/10.1016/j.bmcl.2012.04.131

TY - JOUR

T1 - Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors

AU - Kumar, D. Vijay

AU - Hoarau, Christophe

AU - Bursavich, Matthew

AU - Slattum, Paul

AU - Gerrish, David

AU - Yager, Kraig

AU - Saunders, Michael

AU - Shenderovich, Mark

AU - Roth, Bruce L.

AU - McKinnon, Rena

AU - Chan, Ashley

AU - Cimbora, Daniel M.

AU - Bradford, Chad

AU - Reeves, Leslie

AU - Patton, Scott

AU - Papac, Damon I.

AU - Williams, Brandi L.

AU - Carlson, Robert O.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - 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.

AB - 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.

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UR - https://www.scopus.com/pages/publications/84862190104#tab=citedBy

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DO - 10.1016/j.bmcl.2012.04.131

M3 - Article

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AN - SCOPUS:84862190104

SN - 0960-894X

VL - 22

SP - 4377

EP - 4385

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 13

ER -

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

Abstract

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