Tularik Limited

Amgen Inc.

Kevin Lustig

Bei Shan

Patrick A Baeuerle

Jin-Long Chen

Holger Beckmann

Julio Cesar Medina

Liusheng Zhu

Leping Li

Jiwen Liu

Serena T Cutler

Hirohiko Hasegawa

Methods for identifying modulators of nuclear hormone receptor function comprise the steps of (a) forming a mixture comprising a nuclear hormone receptor, a peptide sensor and a candidate agent, but not a natural coactivator protein of the receptor, wherein the sensor provides direct, in vitro binding to the receptor under assay conditions; (b) measuring an agent-biased binding of the sensor to the receptor; and (c) comparing the agent-biased binding with a corresponding unbiased binding of the sensor to the receptor. In particular embodiments, the sensor comprises an amphipathic alpha helix nuclear hormone interacting domain comprising a recited nuclear hormone transcriptional coactivator motif sequence, the sensor is present at sub-micromolar concentration, the binding reaction occurs in solution, the sensor comprises a fluorescent label and the measuring step comprises detecting fluorescence polarization of the label. Reagents include labeled sensor peptides and reaction mixtures consisting essentially of nuclear hormone receptor, a peptide and a candidate agent.

Nuclear hormone receptor drug screens

Nuclear hormone receptor fluorescence polarization assay

The invention provides compounds, compositions and methods for modulating the effects of LXR in a cell. The compounds and compositions are useful both as diagnostic indicators of LXR function and as pharmacologically active agents. The compounds and compositions find particular use in the treatment of disease states associated with cholesterol metabolism, particularly atherosclerosis and hypercholesterolemia.

LXR modulators

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South San Francisco, CA, United States of America

Kevin Lustig