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

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

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1703-1709
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	12
Issue number	11
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00308
State	Published - Nov 11 2021
Externally published	Yes

Keywords

ERG
Inhibitor
Metastatic castration resistant prostate cancer
Oncogene
Precision medicine
Prostate cancer
RIOK2
SAR
Small molecule
TMPRSS2-ERG

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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title = "New Selective Inhibitors of ERG Positive Prostate Cancer: ERGi-USU-6 Salt Derivatives",

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.",

keywords = "ERG, Inhibitor, Metastatic castration resistant prostate cancer, Oncogene, Precision medicine, Prostate cancer, RIOK2, SAR, Small molecule, TMPRSS2-ERG",

author = "Binil Eldhose and Mallesh Pandrala and Charles Xavier and Mohamed, {Ahmed A.} and Shiv Srivastava and Sunkara, {Anu D.} and Albert Dobi and Malhotra, {Sanjay V.}",

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AU - Eldhose, Binil

AU - Pandrala, Mallesh

AU - Xavier, Charles

AU - Mohamed, Ahmed A.

AU - Srivastava, Shiv

AU - Sunkara, Anu D.

AU - Dobi, Albert

AU - Malhotra, Sanjay V.

N1 - Publisher Copyright: ©

PY - 2021/11/11

Y1 - 2021/11/11

N2 - 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.

AB - 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.

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KW - Metastatic castration resistant prostate cancer

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KW - Small molecule

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

Abstract

Keywords

ASJC Scopus subject areas

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