Abstract:Di(indole)methylarylcarboxylates(DIM-arenes) were designed and synthesized. Competitive binding using labeled 9-cis-retinoic acid showed that DIM-Ph-CF3(BI-1043) bound to the RXRαligand-binding domain (LBD) with an IC50= 14 μM. Replacing the CF3 group by a CO2H group produced DIM-Ph-CO2H (BI-1044) with an IC50= 6 μM. These results and those in transcriptional activation reporter assays suggested that substituted DIM-arenescould function through RXR in exerting their growth inhibitory effects on prostate cancer cells. Computational studies were used to guide structural modifications of the aryl ring to improve binding affinity to RXR in the effort to improve prostate cancer cell growth inhibition. Identification of a more potent RXR ligandmay enhance the efficacy of current prostate cancer therapeutic agents, thereby permitting use at lower doses to reduce adverse systemic effects.

Mao Ye¹,Qiong-Ying Hu¹,Xi-Hua Hu¹,Xiao-Kun Zhang¹,Marcia Dawson¹

¹Cancer Center, Burnham Institute for Medical Research

Keywords: structure-based drug design , prostate cancer , retinoid X receptor (RXR) , synthesis