Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

Abstract

Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG-ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer.

ETS transcription factors as emerging drug targets in cancer

“…Many of the ETS factors, such as ETS1, ERG, FLI1, ETV1, ETV4, and ETV6, already have experimentally determined protein 3D structures (Table ), suitable for structure‐based drug discovery. Figure illustrates the binding pocket of VPC‐18005 on the ETS domain of ERG, and the binding of such a small molecule can block the ERG‐DNA interaction as we previously reported . Similar pockets are also present on ETS factors, including ETS1, ETV4, and ETV6 (Figure B‐D).…”

“…Those target proteins mostly belong to the families of G protein‐coupled receptors, kinases, ion channels, and nuclear receptors . Recent advancements in computational methods of drug discovery and deep learning, as well as exponential growth of available small molecules, make it possible to expand such limited repertoire of drug targets and to consider proteins that have traditionally been deemed as “undruggable.” Our own recent efforts demonstrated that the use of methods of Computer‐Aided Drug Design (CADD) allowed for development of potent and selective inhibitors binding to previously unattended surface‐exposed pockets of such prominent cancer targets as androgen receptor, estrogen receptor, MYC, and ERG (ETS‐related gene) …”

“…As these processes are common between embryogenesis and tumorigenesis, aberrant expression of ETS factors outside normal physiological conditions has been strongly associated with tumor initiation, progression, and metastasis in cancers including prostate cancer, Ewing sarcoma, breast cancer, and leukemia . Importantly, recent discoveries of prototypical ETS inhibitors such as VPC‐18005, YK‐4‐279, BRD32048, and ERGi‐USU have demonstrated that targeting ETS factors may open principally novel and very effective cancer treatment avenues.…”

Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth

“…The emerging strategies to inhibit ERG include direct as well as indirect targeting of ERG (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The ERG-targeted therapies include inhibition of the DNAbinding and transcription activator function of ERG, destabilization of ERG protein, inhibition of CaP-associated ERG mRNA, blocking direct ERG interacting co-activators or the simultaneous disruption of cooperating ERG upstream and downstream factors or its downstream signaling events, including NF-κB or NOTCH (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) April 30, 2018; DOI: 10.1158/0008-5472. CAN-17-2949 Taken together, ERG oncoprotein and the ERG network represent promising, however challenging targets for ERG positive CaP and other cancers.…”

Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

“…Although the prognostic implications of ETS rearrangements remain unclear, recent evidence suggests that TMPRSS2-ERG fusions are associated with young patients and low-grade prostatic cancer [109]. A recent study demonstrates that small molecules targeting the DNA-binding ETS domain of ERG can suppress its transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG [110]. …”