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

31 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

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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.}",

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

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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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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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