A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules

0349788 - BTÚ 2011 RIV US eng J - Journal Article
Zhang, A.X. - Murelli, R.P. - Bařinka, Cyril - Michel, J. - Cocleaza, A. - Jorgensen, W.L. - Lubkowski, J. - Spiegel, D.A.
A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules.
Journal of the American Chemical Society. Roč. 132, č. 36 (2010), s. 12711-12716. ISSN 0002-7863. E-ISSN 1520-5126
Institutional research plan: CEZ:AV0Z50520701
Keywords : Prostate-specific membrane antigen * antibody recruiting molecules * Structure-activity relationship
Subject RIV: CE - Biochemistry
Impact factor: 9.019, year: 2010

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.
Permanent Link: http://hdl.handle.net/11104/0189938