Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer.
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.
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.
Xiaoju
X
Wang
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.
Yuanyuan
Y
Qiao
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.
Irfan A
IA
Asangani
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.
Bushra
B
Ateeq
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.
Anton
A
Poliakov
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.
Marcin
M
Cieślik
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.
Sethuramasundaram
S
Pitchiaya
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.
Balabhadrapatruni V S K
BVSK
Chakravarthi
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.
Xuhong
X
Cao
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.
Xiaojun
X
Jing
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.
Cynthia X
CX
Wang
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.
Ingrid J
IJ
Apel
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.
Rui
R
Wang
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.
Jean Ching-Yi
JC
Tien
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.
Kristin M
KM
Juckette
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.
Wei
W
Yan
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.
Hui
H
Jiang
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.
Shaomeng
S
Wang
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.
Sooryanarayana
S
Varambally
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.
Arul M
AM
Chinnaiyan
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004247:DNA / Q000378:metabolism; D006801:Humans; D008297:Male; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics; D019151:Peptide Library; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000072417:Protein Domains; D000071230:Transcriptional Regulator ERG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C072312:ERG protein, human; D015514:Oncogene Proteins, Fusion; D019151:Peptide Library; D057786:Peptidomimetics; C515553:TMPRSS2-ERG fusion protein, human; D000071230:Transcriptional Regulator ERG; D004247:DNA
ERG transcription factor; peptidomimetic inhibitor; prostate cancer