UNC2025, a Potent
and Orally Bioavailable
MER/FLT3 Dual Inhibitor

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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.

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Most cited references 24

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Targeting Axl and Mer kinases in cancer.

Anupam Verma, Steven L Warner, Hariprasad Vankayalapati … (2011)

Receptor tyrosine kinases (RTK) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. The mammalian TAM RTK family includes 3 closely related members: Tyro-3, Axl, and Mer. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers. Growth arrest-specific gene 6 has been identified as the major ligand for these TAM RTKs, and its binding to the receptors has been shown to promote proliferation and survival of cancer cells in vitro. Abnormal expression and activation of Axl or Mer can provide a survival advantage for certain cancer cells. Inhibition of Axl and Mer may enhance the sensitivity of cancer cells to cytotoxic agents and would potentially be a therapeutic strategy to target cancer cells. This review elucidates the role of Axl and Mer in normal cellular function and their role in oncogenesis. In addition, we review the potential to inhibit these RTKs for the development of therapeutic targets in treatment of cancer.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Chem

Journal ID (iso-abbrev): J. Med. Chem

Journal ID (publisher-id): jm

Journal ID (coden): jmcmar

Title: Journal of Medicinal Chemistry

Publisher: American Chemical Society

ISSN (Print): 0022-2623

ISSN (Electronic): 1520-4804

Publication date PMC-release: 28 July 2015

Publication date (Electronic): 28 July 2014

Publication date (Print): 28 August 2014

Volume: 57

Issue: 16

Pages: 7031-7041

Affiliations

[1] ^†Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, ^‡Department of Pharmacology, School of Medicine, and ^§Lineberger Comprehensive Cancer Center, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States

[∥ ]Department of Pediatrics, School of Medicine, University of Colorado Denver , Aurora, Colorado 80045, United States

[⊥ ]Biological Testing Branch, Developmental Therapeutics Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research , Frederick, Maryland 21702, United States

Author notes

[* ]Tel: 919-843-5486. E-mail: svfrye@ 123456email.unc.edu .

[* ]Tel: 919-843-8456. E-mail: xiaodonw@ 123456unc.edu .

Article

DOI: 10.1021/jm500749d

PMC ID: 4148167

PubMed ID: 25068800

SO-VID: bfec45bc-7729-4853-a0cd-9853ac9f06b4

License:

History

Date received : 14 May 2014

Funding

National Institutes of Health, United States

Custom metadata

document-id-old-9 jm500749d

document-id-new-14 jm-2014-00749d

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ScienceOpen disciplines: Pharmaceutical chemistry

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ScienceOpen disciplines: Pharmaceutical chemistry

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