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J Med Chem. 2009 Jan 8;52(1):14-9. doi: 10.1021/jm800313f.

Selectively targeting T- and B-cell lymphomas: a benzothiazole antagonist of alpha4beta1 integrin.

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  • 1Department of Chemistry, University of California Davis, Davis, California 95616, USA.

Abstract

Current cancer chemotherapeutic agents clinically deployed today are designed to be indiscriminately cytotoxic, however, achieving selective targeting of cancer malignancies would allow for improved diagnostic and chemotherapeutic tools. Integrin alpha(4)beta(1), a heterodimeric cell surface receptor, is believed to have a low-affinity conformation in resting normal lymphocytes and an activated high-affinity conformation in cancerous cells, specifically T- and B-cell lymphomas. This highly attractive yet poorly understood receptor has been selectively targeted with the bisaryl urea peptidomimetic antagonist 1. However, concerns regarding its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzothiazole moiety, resulting in an analogue with improved physicochemical properties, solubility, and kidney:tumor ratio while maintaining potency (6; IC(50) = 53 pM). The results presented herein utilized heterocyclic and solid-phase chemistry, cell adhesion assay, and in vivo optical imaging using the cyanine dye Cy5.5 conjugate.

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