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

Mohamed, Ahmed; Xavier, Charles P.; Sukumar, Gauthaman; Tan, Shyh‐Han; Ravindranath, Lakshmi; Seraj, Nishat; Kumar, Vineet; Sreenath, Taduru; McLeod, David G.; Petrovics, György; Rosner, Inger L.; Srivastava, Meera; Strovel, Jeffrey; Malhotra, Sanjay V.; LaRonde, Nicole A.; Dobi, Albert; Dalgard, Clifton L.; Srivastava, Shiv

doi:10.1158/0008-5472.can-17-2949

Cited by 45 publications

(61 citation statements)

References 49 publications

(39 reference statements)

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“…Screening against 456 kinases via KINOMEscan has identified the ribosomal biogenesis regulator atypical kinase RIOK2, which has the highest binding affinity with the compound ERGi-USU. 21 ERGi-USU treatment in VCaP induced ribosomal stress and reduced ERG protein expression. Two chemical derivatives of ERGi-USU have also showed comparable activity in ERG protein inhibition and VCaP cell growth inhibition.…”

Section: Ergi-usumentioning

confidence: 85%

“…Compound ERGi‐USU (NSC139021) has been identified to inhibit ERG protein expression in VCaP through In‐Cell Western screening of 2407 small molecules, including those from the National Cancer Institute's diversity set . ERGi‐USU inhibited growth of ERG‐positive cancer cell lines including VCaP (prostate cancer), COLO320 (colon cancer), KG‐1 (leukemia), and MOLT‐4 (leukemia).…”

Section: Targeting Ets Factors With Small Moleculesmentioning

confidence: 99%

“…In vivo, it has been shown that ERGi‐USU inhibited growth of ERG‐positive VCaP tumor xenografts with no apparent toxicity in mice treated with 100 and 150 mg/kg dosages, three treatments per week, over 26 days. Screening against 456 kinases via KINOMEscan has identified the ribosomal biogenesis regulator atypical kinase RIOK2, which has the highest binding affinity with the compound ERGi‐USU . ERGi‐USU treatment in VCaP induced ribosomal stress and reduced ERG protein expression.…”

Section: Targeting Ets Factors With Small Moleculesmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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ETS transcription factors as emerging drug targets in cancer

Hsing

Wang

Rennie

et al. 2019

Medicinal Research Reviews

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The ETS family of proteins consists of 28 transcription factors, many of which have been implicated in development and progression of a variety of cancers. While one family member, ERG, has been rigorously studied in the context of prostate cancer where it plays a critical role, other ETS factors keep emerging as potential hallmark oncodrivers. In recent years, numerous studies have reported initial discoveries of small molecule inhibitors of ETS proteins and opened novel avenues for ETS‐directed cancer therapies. This review summarizes the state of the art data on therapeutic targeting of ETS family members and highlights the corresponding drug discovery strategies.

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Section: Ergi-usumentioning

confidence: 85%

Section: Targeting Ets Factors With Small Moleculesmentioning

confidence: 99%

Section: Targeting Ets Factors With Small Moleculesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ETS transcription factors as emerging drug targets in cancer

Hsing

Wang

Rennie

et al. 2019

Medicinal Research Reviews

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“…A peptidomimic inhibitor of ERG fusion protein has been recently described which inhibits VCaP tumor growth in vivo with no apparent toxicity . Another small molecule, that decreases ERG expression by inhibition of the ribosomal biogenesis atypical kinase RIOK2, has been reported which decreases VCaP tumor growth in vivo . YK‐4‐279 is a small molecule that inhibits ERG transcriptional activity and decreases VCaP invasion .…”

Section: Discussionmentioning

confidence: 99%

Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

Shao

Kahraman

et al. 2019

The Prostate

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Background The TMPRSS2/ERG (TE) fusion gene is present in half of the prostate cancers (PCas). The TMPRSS2 and ERG junction of the fusion messenger RNA (mRNA) constitutes a cancer‐specific target. Although docetaxel‐based chemotherapy is the second line of therapy following development resistance to androgen ablation therapies, it is not curative. Therefore, the development of nontoxic novel monotherapies for targeting TE mRNA in PCa patients and for increasing the clinical efficacy of docetaxel treatment are needed. Methods We evaluated multiple approaches to enhance the delivery of TE small interfering RNA (siRNA) containing liposomes including PEGylation, topical treatment with nitroglycerin (NG) to increase permeability and retention, and three different PEG modifications: folate, RGD cyclic peptide, and a bFGF fibroblast growth factor receptor‐targeting peptide. The efficacy of the optimized TE siRNA liposome in combination with docetaxel was then evaluated in vivo with or without topical NG in vivo using a VCaP xenograft model. TE fusion protein knockdown in residual tumors was assessed using Western blotting and immunohistochemistry. Results In vivo therapeutic targeting of TE fusion gene by systemic delivery of RGD‐peptide‐coated liposomal siRNA nanovectors led to sustained target silencing, suppressed tumor growth in xenograft models and enhanced the efficacy of docetaxel chemotherapy. Simultaneous application of the vasodilator NG to the skin further increased tissue the delivery of siRNA and enhanced target knockdown. Conclusion TE‐targeted gene silencing therapy using liposomal nanovectors is a potential therapeutic strategy as a monotherapy and to enhance the efficacy of chemotherapy in patients with advanced PCa.

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ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations

Lee

Gutierrez-Lanz

Xiao

et al. 2022

Genes Chromosomes & Cancer

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ERG is a transcription factor encoded on chromosome 21q22.2 with important roles in hematopoiesis and oncogenesis of prostate cancer. ERG amplification has been identified as one of the most common recurrent events in acute myeloid leukemia with complex karyotype (AML‐CK). In this study, we uncover three different modes of ERG amplification in AML‐CK. Importantly, we present evidence to show that ERG amplification is distinct from intrachromosomal amplification of chromosome 21 (iAMP21), a hallmark segmental amplification frequently encompassing RUNX1 and ERG in a subset of high‐risk B‐lymphoblastic leukemia. We also characterize the association with TP53 aberrations and other chromosomal aberrations, including chromothripsis. Lastly, we show that ERG amplification can initially emerge as subclonal events in low‐grade myeloid neoplasms. These findings demonstrate that ERG amplification is a recurrent secondary driver event in AML and raise the tantalizing possibility of ERG as a therapeutic target.

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

Cited by 45 publications

References 49 publications

ETS transcription factors as emerging drug targets in cancer

ETS transcription factors as emerging drug targets in cancer

Targeting the TMPRSS2/ERG fusion mRNA using liposomal nanovectors enhances docetaxel treatment in prostate cancer

ERG amplification is a secondary recurrent driver event in myeloid malignancy with complex karyotype and TP53 mutations

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