New Selective Inhibitors of ERG Positive Prostate Cancer: ERGi-USU-6 Salt Derivatives

Binil Eldhose; Mallesh Pandrala; Charles Xavier; Ahmed A Mohamed; Shiv Srivastava; Anu D Sunkara; Albert Dobi; Sanjay V Malhotra

doi:10.1021/acsmedchemlett.1c00308

New Selective Inhibitors of ERG Positive Prostate Cancer: ERGi-USU-6 Salt Derivatives

ACS Med Chem Lett. 2021 Oct 19;12(11):1703-1709. doi: 10.1021/acsmedchemlett.1c00308. eCollection 2021 Nov 11.

Authors

Binil Eldhose^{1

2}, Mallesh Pandrala^{3

3

4}, Charles Xavier^{1

2}, Ahmed A Mohamed^{1

2}, Shiv Srivastava¹, Anu D Sunkara^{1

5}, Albert Dobi^{1

2}, Sanjay V Malhotra^{3

3

4}

Affiliations

¹ Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889, United States.
² Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland 20817, United States.
³ Department of Cell, Developmental and Cancer Biology, Center for Experimental Therapeutics, Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97201, United States.
⁴ Division of Radiation & Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, United States.
⁵ Washington Adventist University, Takoma Park, Maryland 20912, United States.

Abstract

Prostate cancer is among the leading causes of cancer related death of men in the United States. The ERG gene fusion leading to overexpression of near full-length ERG transcript and protein represents most prevalent (50-65%) prostate cancer driver gene alterations. The ERG oncoprotein overexpression persists in approximately 35% of metastatic castration resistant prostate cancers. Due to the emergence of eventual refractoriness to second- and third-generation androgen axis-based inhibitors, there remains a pressing need to develop drugs targeting other validated prostate cancer drivers such as ERG. Here we report the new and more potent ERG inhibitor ERGi-USU-6 developed by structure-activity studies from the parental ERGi-USU. We have developed an improved procedure for the synthesis of ERGi-USU-6 and identified a salt formulation that further improves its activity in biological assays for selective targeting of ERG harboring prostate cancer cells.