Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer

Xiaoju Wang; Yuanyuan Qiao; Irfan A Asangani; Bushra Ateeq; Anton Poliakov; Marcin Cieślik; Sethuramasundaram Pitchiaya; Balabhadrapatruni V S K Chakravarthi; Xuhong Cao; Xiaojun Jing; Cynthia X Wang; Ingrid J Apel; Rui Wang; Jean Ching-Yi Tien; Kristin M Juckette; Wei Yan; Hui Jiang; Shaomeng Wang; Sooryanarayana Varambally; Arul M Chinnaiyan

doi:10.1016/j.ccell.2017.02.017

Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer

Cancer Cell. 2017 Apr 10;31(4):532-548.e7. doi: 10.1016/j.ccell.2017.02.017. Epub 2017 Mar 23.

Authors

Xiaoju Wang¹, Yuanyuan Qiao², Irfan A Asangani², Bushra Ateeq³, Anton Poliakov², Marcin Cieślik², Sethuramasundaram Pitchiaya², Balabhadrapatruni V S K Chakravarthi⁴, Xuhong Cao², Xiaojun Jing², Cynthia X Wang², Ingrid J Apel², Rui Wang², Jean Ching-Yi Tien², Kristin M Juckette², Wei Yan², Hui Jiang⁵, Shaomeng Wang⁶, Sooryanarayana Varambally⁷, Arul M Chinnaiyan⁸

Affiliations

¹ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
² Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
³ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Biological Sciences & Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, UP, India.
⁴ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁵ Department of Biostatistics, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
⁶ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Medicinal Chemistry, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
⁸ Michigan Center for Translational Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, 1400 East Medical Center Drive, 5316 CCGC, Ann Arbor, MI 48109, USA. Electronic address: arul@umich.edu.

Abstract

Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies.

Keywords: ERG transcription factor; peptidomimetic inhibitor; prostate cancer.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Chick Embryo
DNA / metabolism
Humans
Male
Mice, Nude
Neovascularization, Physiologic / drug effects
Oncogene Proteins, Fusion / antagonists & inhibitors*
Oncogene Proteins, Fusion / genetics
Peptide Library
Peptidomimetics / chemistry
Peptidomimetics / pharmacology*
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / genetics
Prostatic Neoplasms / pathology
Protein Domains
Transcriptional Regulator ERG / antagonists & inhibitors
Transcriptional Regulator ERG / genetics
Transcriptional Regulator ERG / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
ERG protein, human
Oncogene Proteins, Fusion
Peptide Library
Peptidomimetics
TMPRSS2-ERG fusion protein, human
Transcriptional Regulator ERG
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding