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A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules
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SYSNO ASEP 0349788 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules Author(s) Zhang, A.X. (US)
Murelli, R.P. (US)
Bařinka, Cyril (BTO-N) RID, ORCID
Michel, J. (US)
Cocleaza, A. (US)
Jorgensen, W.L. (US)
Lubkowski, J. (US)
Spiegel, D.A. (US)Source Title Journal of the American Chemical Society. - : American Chemical Society - ISSN 0002-7863
Roč. 132, č. 36 (2010), s. 12711-12716Number of pages 6 s. Language eng - English Country US - United States Keywords Prostate-specific membrane antigen ; antibody recruiting molecules ; Structure-activity relationship Subject RIV CE - Biochemistry CEZ AV0Z50520701 - BTO-N (2007-2013) UT WOS 000282074200036 DOI 10.1021/ja104591m Annotation Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. We have recently disclosed a class of small molecules called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs and drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2011
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