The androgen receptor (AR) plays a pivotal role in the development of the prostate gland. It also has relations with the occurrence and progression of prostate cancer (PCa). AR is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). With recurrent or metastatic PCa,  the first line of treatment is some form of androgen withdrawal therapy. It blocks either the production of androgens or their binding to the AR. Unfortunately, the effectiveness of this approach is usually temporary due to the progression of surviving tumor cells to the castration-resistant state. There is an urgent need for novel therapeutic strategies to modulate AR. They include direct disruption of its critical interactions with co-activator proteins, mediated by Activation Function 2 (AF2) and Binding Function 3 (BF3) surface sites. CLP-3094 is a potent BF3 inhibitor of AR. CLP-3094 inhibits AR transcriptional activity. It is also a selective, potent GPR142 antagonist.

CLP-3094 is a potent BF3 inhibitor of AR and a selective, potent GPR142 antagonist.

CLP-3094 inhibits AR transcriptional activity (IC50=4 μM). In addition, CLP-3094 inhibits both an increase of intracellular Ca2+ concentration ([Ca2+]i) induced by L-tryptophan using CHO-K1 cells expressing GPR142 in the aequorin assay, and an accumulation of inositol phosphates using HEK293 cells expressing GPR142 in the SPA assay. The IC50 of CLP-3094 is 0.2 μM against 200 μM L-tryptophanfor the mouse receptor and 2.3 μM against 1 mM L-tryptophan for the human receptor in the aequorin assay. Moreover, CLP-3094 also inhibits the insulin secretion from islets induced by both L-tryptophan and GPR142 agonists. It also consistently displayed significantly lower severity of arthritis scores than vehicle-treated mice. Thus, CLP-3094 has the potential for the treatment of chronic inflammatory diseases.

In summary, CLP-3094 is a potent BF3 inhibitor of the AR and also a selective, potent GPR142 antagonist.


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