Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

B. Barry Toure; John Giraldes; Troy Smith; Elizabeth R. Sprague; Yaping Wang; Simon Mathieu; Zhuoliang Chen; Yuji Mishina; Yun Feng; Yan Yan-Neale; Subarna Shakya; Dongshu Chen; Matthew Meyer; David Puleo; J. Tres Brazell; Christopher Straub; David Sage; Kirk Wright; Yanqiu Yuan; Xin Chen; Jose Duca; Sean Kim; Li Tian; Eric Martin; Kristen Hurov; Wenlin Shao

doi:10.1021/acs.jmedchem.6b00052

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

B. Barry Toure, John Giraldes, Troy Smith, Elizabeth R. Sprague, Yaping Wang, Simon Mathieu, Zhuoliang Chen, Yuji Mishina, Yun Feng, Yan Yan-Neale, Subarna Shakya, Dongshu Chen, Matthew Meyer, David Puleo, J. Tres Brazell, Christopher Straub, David Sage, Kirk Wright, Yanqiu Yuan, Xin ChenJose Duca, Sean Kim, Li Tian, Eric Martin, Kristen Hurov, Wenlin Shao

Glycomics Program

25 Citations (Scopus)

Abstract

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	10
Pages (from-to)	4711-4723
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.6b00052
Publication status	Published - 26 May 2016

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Toure, B. B., Giraldes, J., Smith, T., Sprague, E. R., Wang, Y., Mathieu, S., Chen, Z., Mishina, Y., Feng, Y., Yan-Neale, Y., Shakya, S., Chen, D., Meyer, M., Puleo, D., Brazell, J. T., Straub, C., Sage, D., Wright, K., Yuan, Y., ... Shao, W. (2016). Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. Journal of Medicinal Chemistry, 59(10), 4711-4723. https://doi.org/10.1021/acs.jmedchem.6b00052

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. / Toure, B. Barry; Giraldes, John; Smith, Troy et al.

In: Journal of Medicinal Chemistry, Vol. 59, No. 10, 26.05.2016, p. 4711-4723.

Research output: Contribution to journal › Journal article › Research › peer-review

Toure, BB, Giraldes, J, Smith, T, Sprague, ER, Wang, Y, Mathieu, S, Chen, Z, Mishina, Y, Feng, Y, Yan-Neale, Y, Shakya, S, Chen, D, Meyer, M, Puleo, D, Brazell, JT, Straub, C, Sage, D, Wright, K, Yuan, Y, Chen, X, Duca, J, Kim, S, Tian, L, Martin, E, Hurov, K & Shao, W 2016, 'Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight', Journal of Medicinal Chemistry, vol. 59, no. 10, pp. 4711-4723. https://doi.org/10.1021/acs.jmedchem.6b00052

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title = "Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight",

abstract = "MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.",

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AU - Toure, B. Barry

AU - Giraldes, John

AU - Smith, Troy

AU - Sprague, Elizabeth R.

AU - Wang, Yaping

AU - Mathieu, Simon

AU - Chen, Zhuoliang

AU - Mishina, Yuji

AU - Feng, Yun

AU - Yan-Neale, Yan

AU - Shakya, Subarna

AU - Chen, Dongshu

AU - Meyer, Matthew

AU - Puleo, David

AU - Brazell, J. Tres

AU - Straub, Christopher

AU - Sage, David

AU - Wright, Kirk

AU - Yuan, Yanqiu

AU - Chen, Xin

AU - Duca, Jose

AU - Kim, Sean

AU - Tian, Li

AU - Martin, Eric

AU - Hurov, Kristen

AU - Shao, Wenlin

PY - 2016/5/26

Y1 - 2016/5/26

N2 - MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

AB - MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

U2 - 10.1021/acs.jmedchem.6b00052

DO - 10.1021/acs.jmedchem.6b00052

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C2 - 27187609

SN - 0022-2623

VL - 59

SP - 4711

EP - 4723

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

Abstract

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