title: Identification of initial leads directed at the calmodulin-binding region on the Src-SH2 domain that exhibit anti-proliferation activity against pancreatic cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Ywh-Min
authors.initials: YM
authors.lastname: Tzou
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Yuan
authors.affiliation: 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.
authors.forename: Ronald
authors.initials: R
authors.lastname: Shin
authors.affiliation: Southern Research, Birmingham, AL 35205, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, United States.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Vivo Biosciences, Inc., 1601 12th Ave South, Birmingham, AL 35205, United States.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Lalita A
authors.initials: LA
authors.lastname: Shevde
authors.affiliation: 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.
authors.forename: N Rama
authors.initials: NR
authors.lastname: Krishna
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D002151:Calorimetry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D018909:src Homology Domains; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002147:Calmodulin; D019061:src-Family Kinases
keywords: 3D-microtumors; AsPC-1; BxPC-3; ITC; Inhibitors; Initial leads; MCF10A; MiaPaCa-2; NMR; Pancreatic cancer