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^*

^*Corresponding author for this work

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

3 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
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 - 11 Nov 2021
Externally published	Yes

Keywords

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

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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.}",

note = "Funding Information: This research was supported by the CPDR-USU program HU0001-20-2-0032, the USU & HJF Office of Technology Transfer FY2015 IP Development Award to S.S. and A.D. and the John P. Murtha Cancer Center Translational Research Fellowship Award to C.X. under the mentorship of S.S. and S.V.M. Publisher Copyright: {\textcopyright} ",

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language = "English",

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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 - Funding Information: This research was supported by the CPDR-USU program HU0001-20-2-0032, the USU & HJF Office of Technology Transfer FY2015 IP Development Award to S.S. and A.D. and the John P. Murtha Cancer Center Translational Research Fellowship Award to C.X. under the mentorship of S.S. and S.V.M. Publisher Copyright: ©

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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 - Small molecule

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

Abstract

Keywords

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