MP87-14 STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF ERGI-USU, A HIGHLY SELECTIVE INHIBITOR FOR ERG POSITIVE PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2017MP87-14 STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF ERGI-USU, A HIGHLY SELECTIVE INHIBITOR FOR ERG POSITIVE PROSTATE CANCER CELLS Ahmed Mohamed, Charles Xavier, Gauthaman Sukumar, Samuel Banister, Vineet Kumar, Shyh-Han Tan, Shilpa Katta, Lakshmi Ravindranath, Muhammad Jamal, Taduru Sreenath, David McLeod, Gyorgy Petrovics, Albert Dobi, Meera Srivastava, Sanjay Malhotra, Clifton Dalgard, and Shiv Srivastava Ahmed MohamedAhmed Mohamed More articles by this author , Charles XavierCharles Xavier More articles by this author , Gauthaman SukumarGauthaman Sukumar More articles by this author , Samuel BanisterSamuel Banister More articles by this author , Vineet KumarVineet Kumar More articles by this author , Shyh-Han TanShyh-Han Tan More articles by this author , Shilpa KattaShilpa Katta More articles by this author , Lakshmi RavindranathLakshmi Ravindranath More articles by this author , Muhammad JamalMuhammad Jamal More articles by this author , Taduru SreenathTaduru Sreenath More articles by this author , David McLeodDavid McLeod More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , Albert DobiAlbert Dobi More articles by this author , Meera SrivastavaMeera Srivastava More articles by this author , Sanjay MalhotraSanjay Malhotra More articles by this author , Clifton DalgardClifton Dalgard More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2718AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES While new prostate cancer (CaP) treatments (Abiraterone and Enzalutamide) have improved survival in castration resistant prostate cancer (CRPC), their benefits are short-lived and drug resistance develops likely due to numerous adaptive mutations. Accumulating evidence has established the androgen regulated TMPRSS2-ERG fusion as a common oncogenic driver that contributes to the early development and progression of over half of CaP. Therefore, ERG oncoprotein and ERG dependent pathways are promising targets for CaP therapy in early stages when cancer is most responsive to treatment. We previously identified a small molecule inhibitor, ERGi-USU, which selectively inhibits ERG protein and cell growth in ERG positive tumor cell lines and mouse xenograft models. In an effort to further develop ERGi-USU with enhanced efficacy we performed detailed structure-activity relationship (SAR) evaluation of ERGi-USU core structure and developed new derivatives. METHODS Based on SAR of the core structure of ERGi-USU, 48 new derivatives were designed and synthesized by substitutions with alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or hydroxyl groups. The new ERGi-USU derivatives were evaluated for inhibition of cell growth and ERG protein levels in the TMPRSS2-ERG fusion harboring CaP cell line, VCaP. Four of these compounds have been selected for evaluation of ERG selectivity by defining IC50 in ERG positive malignant cells (VCaP, KG1, MOLT-4 and COLO320), ERG negative CaP cell line (LNCaP) or ERG positive normal primary endothelium-derived cells (HUVEC). RESULTS Like parental compound, four new ERGi-USU derivatives exhibited inhibition of cell growth and ERG protein levels in ERG positive VCaP, KG1, MOLT-4 and COLO320 cell lines, with no or minimal effects on LNCaP and HUVEC cells. One of the new derivatives (ERGi-USU#6) showed increased efficacy for cell growth inhibition (IC50=0.074μM) compared to the parental ERGi-USU (IC50=0.200μM). Other three new compounds showed similar IC50 as the ERGi-USU. CONCLUSIONS Comprehensive evaluation of ERGi-USU derivatives along with parental compound has continued to underscore selective inhibition of ERG positive tumor cells by these small molecules. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1171 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ahmed Mohamed More articles by this author Charles Xavier More articles by this author Gauthaman Sukumar More articles by this author Samuel Banister More articles by this author Vineet Kumar More articles by this author Shyh-Han Tan More articles by this author Shilpa Katta More articles by this author Lakshmi Ravindranath More articles by this author Muhammad Jamal More articles by this author Taduru Sreenath More articles by this author David McLeod More articles by this author Gyorgy Petrovics More articles by this author Albert Dobi More articles by this author Meera Srivastava More articles by this author Sanjay Malhotra More articles by this author Clifton Dalgard More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...