UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

Weihe Zhang; Deborah Deryckere; Debra Hunter; Jing Liu; Michael A. Stashko; Katherine A. Minson; Christopher T. Cummings; Minjung Lee; Trevor G. Glaros; Dianne L. Newton; Susan Sather; Dehui Zhang; Dmitri Kireev; William P. Janzen; H. Shelton Earp; Douglas K. Graham; Stephen V. Frye; Xiaodong Wang

doi:10.1021/jm500749d

UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

Weihe Zhang, Deborah Deryckere, Debra Hunter, Jing Liu, Michael A. Stashko, Katherine A. Minson, Christopher T. Cummings, Minjung Lee, Trevor G. Glaros, Dianne L. Newton, Susan Sather, Dehui Zhang, Dmitri Kireev, William P. Janzen, H. Shelton Earp, Douglas K. Graham, Stephen V. Frye, Xiaodong Wang

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

116 Scopus citations

Abstract

We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

Original language	English (US)
Pages (from-to)	7031-7041
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	16
DOIs	https://doi.org/10.1021/jm500749d
State	Published - Aug 28 2014
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Zhang, W., Deryckere, D., Hunter, D., Liu, J., Stashko, M. A., Minson, K. A., Cummings, C. T., Lee, M., Glaros, T. G., Newton, D. L., Sather, S., Zhang, D., Kireev, D., Janzen, W. P., Earp, H. S., Graham, D. K., Frye, S. V., & Wang, X. (2014). UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor. Journal of Medicinal Chemistry, 57(16), 7031-7041. https://doi.org/10.1021/jm500749d

Zhang, W, Deryckere, D, Hunter, D, Liu, J, Stashko, MA, Minson, KA, Cummings, CT, Lee, M, Glaros, TG, Newton, DL, Sather, S, Zhang, D, Kireev, D, Janzen, WP, Earp, HS, Graham, DK, Frye, SV & Wang, X 2014, 'UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor', Journal of Medicinal Chemistry, vol. 57, no. 16, pp. 7031-7041. https://doi.org/10.1021/jm500749d

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title = "UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor",

abstract = "We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.",

author = "Weihe Zhang and Deborah Deryckere and Debra Hunter and Jing Liu and Stashko, {Michael A.} and Minson, {Katherine A.} and Cummings, {Christopher T.} and Minjung Lee and Glaros, {Trevor G.} and Newton, {Dianne L.} and Susan Sather and Dehui Zhang and Dmitri Kireev and Janzen, {William P.} and Earp, {H. Shelton} and Graham, {Douglas K.} and Frye, {Stephen V.} and Xiaodong Wang",

year = "2014",

month = aug,

day = "28",

doi = "10.1021/jm500749d",

language = "English (US)",

volume = "57",

pages = "7031--7041",

journal = "Journal of Medicinal Chemistry",

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publisher = "American Chemical Society",

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T1 - UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

AU - Zhang, Weihe

AU - Deryckere, Deborah

AU - Hunter, Debra

AU - Liu, Jing

AU - Stashko, Michael A.

AU - Minson, Katherine A.

AU - Cummings, Christopher T.

AU - Lee, Minjung

AU - Glaros, Trevor G.

AU - Newton, Dianne L.

AU - Sather, Susan

AU - Zhang, Dehui

AU - Kireev, Dmitri

AU - Janzen, William P.

AU - Earp, H. Shelton

AU - Graham, Douglas K.

AU - Frye, Stephen V.

AU - Wang, Xiaodong

PY - 2014/8/28

Y1 - 2014/8/28

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AB - We previously reported a potent small molecule Mer tyrosine kinase inhibitor UNC1062. However, its poor PK properties prevented further assessment in vivo. We report here the sequential modification of UNC1062 to address DMPK properties and yield a new potent and highly orally bioavailable Mer inhibitor, 11, capable of inhibiting Mer phosphorylation in vivo, following oral dosing as demonstrated by pharmaco-dynamic (PD) studies examining phospho-Mer in leukemic blasts from mouse bone marrow. Kinome profiling versus more than 300 kinases in vitro and cellular selectivity assessments demonstrate that 11 has similar subnanomolar activity against Flt3, an additional important target in acute myelogenous leukemia (AML), with pharmacologically useful selectivity versus other kinases examined.

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

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ER -

UNC2025, a potent and orally bioavailable MER/FLT3 dual inhibitor

Abstract

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