Selectively targeting T- and B-cell lymphomas: A benzothiazole antagonist of α 4β 1integrin

Richard D. Carpenter, Mirela Andrei, Olulanu H. Aina, Edmond Y Lau, Felice C Lightstone, Ruiwu Liu, Kit Lam, Mark J. Kurth

Research output: Contribution to journalArticle

27 Scopus citations

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 α 41, 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 i. 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.

Original languageEnglish (US)
Pages (from-to)14-19
Number of pages6
JournalJournal of Medicinal Chemistry
Volume52
Issue number1
DOIs
StatePublished - Jan 8 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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