UNC1062, a new and potent Mer inhibitor

Jing Liu; Weihe Zhang; Michael A. Stashko; Deborah DeRyckere; Christopher T. Cummings; Debra Hunter; Chao Yang; Chatura N. Jayakody; Nancy Cheng; Catherine Simpson; Jacqueline Norris-Drouin; Susan Sather; Dmitri Kireev; William P. Janzen; H. Shelton Earp; Douglas K. Graham; Stephen V. Frye; Xiaodong Wang

doi:10.1016/j.ejmech.2013.03.035

UNC1062, a new and potent Mer inhibitor

Jing Liu
, Weihe Zhang
, Michael A. Stashko
, Deborah DeRyckere
, Christopher T. Cummings
, Debra Hunter
, Chao Yang
, Chatura N. Jayakody
, Nancy Cheng
, Catherine Simpson
, Jacqueline Norris-Drouin
, Susan Sather
, Dmitri Kireev
, William P. Janzen
, H. Shelton Earp
, Douglas K. Graham
, Stephen V. Frye
, Xiaodong Wang

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

64 Scopus citations

Abstract

Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC₅₀ = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

Original language	English
Pages (from-to)	83-93
Number of pages	11
Journal	European Journal of Medicinal Chemistry
Volume	65
DOIs	https://doi.org/10.1016/j.ejmech.2013.03.035
State	Published - 2013
Externally published	Yes

Keywords

Glioblastoma
Leukemia
Mer inhibitors
Non-small cell lung cancer
Pyrazolopyrimidines
Sulfonamides

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10.1016/j.ejmech.2013.03.035

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Liu, J., Zhang, W., Stashko, M. A., DeRyckere, D., Cummings, C. T., Hunter, D., Yang, C., Jayakody, C. N., Cheng, N., Simpson, C., Norris-Drouin, J., Sather, S., Kireev, D., Janzen, W. P., Earp, H. S., Graham, D. K., Frye, S. V., & Wang, X. (2013). UNC1062, a new and potent Mer inhibitor. European Journal of Medicinal Chemistry, 65, 83-93. https://doi.org/10.1016/j.ejmech.2013.03.035

@article{b313852b12cb46e69efcc975c3586b3b,

title = "UNC1062, a new and potent Mer inhibitor",

abstract = "Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.",

keywords = "Glioblastoma, Leukemia, Mer inhibitors, Non-small cell lung cancer, Pyrazolopyrimidines, Sulfonamides",

author = "Jing Liu and Weihe Zhang and Stashko, \{Michael A.\} and Deborah DeRyckere and Cummings, \{Christopher T.\} and Debra Hunter and Chao Yang and Jayakody, \{Chatura N.\} and Nancy Cheng and Catherine Simpson and Jacqueline Norris-Drouin and Susan Sather and Dmitri Kireev and Janzen, \{William P.\} and Earp, \{H. Shelton\} and Graham, \{Douglas K.\} and Frye, \{Stephen V.\} and Xiaodong Wang",

note = "Funding Information: HERG data was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract \# HHSN-271-2008-025C(NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. We also thank Yingqiu Zhou for her help with MCE assays. This work was supported by the University of North Carolina Cancer Research Fund and Federal Funds from the National Cancer Institute, National Institute of Health , under Contract No. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. ",

year = "2013",

doi = "10.1016/j.ejmech.2013.03.035",

language = "English",

volume = "65",

pages = "83--93",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

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TY - JOUR

T1 - UNC1062, a new and potent Mer inhibitor

AU - Liu, Jing

AU - Zhang, Weihe

AU - Stashko, Michael A.

AU - DeRyckere, Deborah

AU - Cummings, Christopher T.

AU - Hunter, Debra

AU - Yang, Chao

AU - Jayakody, Chatura N.

AU - Cheng, Nancy

AU - Simpson, Catherine

AU - Norris-Drouin, Jacqueline

AU - Sather, Susan

AU - Kireev, Dmitri

AU - Janzen, William P.

AU - Earp, H. Shelton

AU - Graham, Douglas K.

AU - Frye, Stephen V.

AU - Wang, Xiaodong

N1 - Funding Information: HERG data was generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # HHSN-271-2008-025C(NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscol at NIMH, Bethesda MD, USA. We also thank Yingqiu Zhou for her help with MCE assays. This work was supported by the University of North Carolina Cancer Research Fund and Federal Funds from the National Cancer Institute, National Institute of Health , under Contract No. HHSN261200800001E . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

PY - 2013

Y1 - 2013

N2 - Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

AB - Abnormal activation of Mer kinase has been implicated in the oncogenesis of many human cancers including acute lymphoblastic and myeloid leukemia, non-small cell lung cancer, and glioblastoma. We have discovered a new family of small molecule Mer inhibitors, pyrazolopyrimidine sulfonamides, that potently inhibit the kinase activity of Mer. Importantly, these compounds do not demonstrate significant hERG activity in the PatchXpress assay. Through structure-activity relationship studies, 35 (UNC1062) was identified as a potent (IC50 = 1.1 nM) and selective Mer inhibitor. When applied to live tumor cells, UNC1062 inhibited Mer phosphorylation and colony formation in soft agar. Given the potential of Mer as a therapeutic target, UNC1062 is a promising candidate for further drug development.

KW - Glioblastoma

KW - Leukemia

KW - Mer inhibitors

KW - Non-small cell lung cancer

KW - Pyrazolopyrimidines

KW - Sulfonamides

UR - https://www.scopus.com/pages/publications/84877845714

U2 - 10.1016/j.ejmech.2013.03.035

DO - 10.1016/j.ejmech.2013.03.035

M3 - Article

AN - SCOPUS:84877845714

SN - 0223-5234

VL - 65

SP - 83

EP - 93

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

UNC1062, a new and potent Mer inhibitor

Abstract

Keywords

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