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 4&β 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 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 language | English (US) |
|---|---|
| Pages (from-to) | 14-19 |
| Number of pages | 6 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 52 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 8 2009 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Selectively targeting T- and B-cell lymphomas : A benzothiazole antagonist of α 4β 1integrin. / Carpenter, Richard D.; Andrei, Mirela; Aina, Olulanu H.; Lau, Edmond Y; Lightstone, Felice C; Liu, Ruiwu; Lam, Kit; Kurth, Mark J.
In: Journal of Medicinal Chemistry, Vol. 52, No. 1, 08.01.2009, p. 14-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Selectively targeting T- and B-cell lymphomas
T2 - A benzothiazole antagonist of α 4β 1integrin
AU - Carpenter, Richard D.
AU - Andrei, Mirela
AU - Aina, Olulanu H.
AU - Lau, Edmond Y
AU - Lightstone, Felice C
AU - Liu, Ruiwu
AU - Lam, Kit
AU - Kurth, Mark J.
PY - 2009/1/8
Y1 - 2009/1/8
N2 - 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 4&β 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 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.
AB - 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 4&β 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 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=59449093689&partnerID=8YFLogxK
U2 - 10.1021/jm800313f
DO - 10.1021/jm800313f
M3 - Article
C2 - 19072684
AN - SCOPUS:59449093689
VL - 52
SP - 14
EP - 19
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 1
ER -