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Selectively Targeting T- and B-Cell Lymphomas: A Benzothiazole Antagonist of α4β1 Integrin
- Source :
- Journal of Medicinal Chemistry. 52:14-19
- Publication Year :
- 2008
- Publisher :
- American Chemical Society (ACS), 2008.
-
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.
- Subjects :
- Male
Lymphoma, B-Cell
Peptidomimetic
Cell
Mice, Nude
Integrin alpha4beta1
Lymphoma, T-Cell
Article
Substrate Specificity
Inhibitory Concentration 50
Mice
Structure-Activity Relationship
Cell surface receptor
Cell Line, Tumor
Drug Discovery
Cell Adhesion
medicine
Animals
Humans
Cytotoxic T cell
Benzothiazoles
Cell adhesion
Receptor
B cell
Molecular Structure
Chemistry
Xenograft Model Antitumor Assays
medicine.anatomical_structure
Biochemistry
Cancer research
Molecular Medicine
Female
Pharmacophore
Sesquiterpenes
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 52
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....53f7742279badfd7ee45bfd2ccc10dbe