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Bioorg Med Chem Lett. 2016 Feb 15;26(4):1237-44. doi: 10.1016/j.bmcl.2016.01.027. Epub 2016 Jan 12.

Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer.

Author information

1
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
2
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
3
Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
4
Southern Research, Birmingham, AL 35205, United States.
5
Vivo Biosciences, Inc., 1601 12th Ave South, Birmingham, AL 35205, United States.
6
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
7
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, United States. Electronic address: nrk@uab.edu.

Abstract

Cellular calmodulin binds to the SH2 domain of Src kinase, and upon Fas activation it recruits Src into the death-inducing signaling complex. This results in Src-ERK activation of cell survival pathway through which pancreatic cancer cells survive and proliferate. We had proposed that the inhibition of the interaction of calmodulin with Src-SH2 domain is an attractive strategy to inhibit the proliferation of pancreatic cancer. Thus we have performed screening of compound libraries by a combination of methods and identified some compounds (initial leads) that target the calmodulin-binding region on the SH2 domain and inhibit the proliferation of pancreatic cancer cells in in vitro assays. Most of these compounds also exhibited varying degrees of cytotoxicity when tested against immortalized breast epithelial cell line (MCF10A). These initial leads are likely candidates for development in targeted delivery of compounds to cancer cells without affecting normal cells.

KEYWORDS:

3D-microtumors; AsPC-1; BxPC-3; ITC; Inhibitors; Initial leads; MCF10A; MiaPaCa-2; NMR; Pancreatic cancer

PMID:
26803204
PMCID:
PMC4747798
DOI:
10.1016/j.bmcl.2016.01.027
[Indexed for MEDLINE]
Free PMC Article

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