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

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 prostatecancer) 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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 prostatecancer) 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.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

CE - Biochemie

OECD FORD obor

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Projekt

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Návaznosti

Z - Vyzkumny zamer (s odkazem do CEZ)

Rok uplatnění

2010

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of the American Chemical Society

ISSN

0002-7863

e-ISSN

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Svazek periodika

132

Číslo periodika v rámci svazku

36

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

6

Strana od-do

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Kód UT WoS článku

000282074200036

EID výsledku v databázi Scopus

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