Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex

Dubey, Ramin; Levin, Michael D; Szabó, Lajos; László, Csaba; Kushal, Swati; Singh, Jason; Oh, Philip; Schnitzer, Jan E.; Olenyuk, Bogdan

doi:10.1021/ja400805b

Cited by 51 publications

(48 citation statements)

References 79 publications

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“…A fluorescence polarization assay was used to evaluate the ability of HBS 1 to inhibit the binding of fluorescein-labeled HIF-1α C-TAD 786-826 domain to p300-CH1 (32,33). Addition of 1 to the preformed protein complex provided a concentration-dependent decrease in fluorescence polarization, with an inhibitory constant, K i = 3.5 ± 1.2 μM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HBS 1 is an efficient modulator of contacts between HIF-1α and p300/CBP. Known inhibitors of this interaction typically function allosterically, by inducing unfolding of p300/CBP through abstraction of zinc ions (27,33,38,39), which could lead to nonspecific abstraction of metal ions from other biomolecules. We predicted that our HIF-1α mimetics should manifest their function in a more specific manner, and should not be generally cytotoxic (9).…”

Section: Resultsmentioning

confidence: 99%

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Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

Kushal

Lao

Henchey

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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131

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Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth.helix mimetics | synthetic inhibitors of transcription | rational design | hydrogen bond surrogate helices

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

Kushal

Lao

Henchey

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

131

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“…Dimeric epidithiodiketopiperazines (ETPs) are recent examples of allosteric small-molecule inhibitors of the HIF complex that also target the p300 CH1 domain (20,23). Treatment of hypoxic MCF7 cells with dimeric ETP 2 resulted in at least twofold expression changes in 329 genes (SI Appendix, Table S2) (20).…”

Section: Design and Synthesis Of Topographical Hif1αmentioning

confidence: 99%

“…Inhibitors of hypoxia-inducible gene expression would serve as unique tools for dissecting hypoxia signaling in tumors, as well as leads for cancer therapeutics (16)(17)(18)(19)(20)(21)(22)(23)(24)(25). The transcription factorcoactivator interaction presents an intriguing target for controlling hypoxia signaling because it is a critical node directing downstream expression of various genes that work in concert to modulate cancer progression.…”

mentioning

confidence: 99%

In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

Lao

Grishagin

Mesallati

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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126

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Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces. We describe the design, synthesis, biochemical, and in vivo evaluation of a small-molecule scaffold that captures the topography of α-helices. We designed mimics of a key α-helical domain at the interface of hypoxia-inducible factor 1α and p300 to develop inhibitors of hypoxia-inducible signaling. The hypoxia-inducible factor/ p300 interaction regulates the transcription of key genes, whose expression contributes to angiogenesis, metastasis, and altered energy metabolism in cancer. The designed compounds target the desired protein with high affinity and in a predetermined manner, with the optimal ligand providing effective reduction of tumor burden in experimental animal models.helix mimics | hypoxia signaling | synthetic inhibitors of transcription

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“…41 Our results show that targeting HIF-1a leads to reduced c-MET protein levels, which corroborates the results of studies that have shown that this also occurs in breast and lung cancer cell lines. 12 It may be that disrupting HIF-1 function in gliomas, and thus c-MET, will not lead to the same invasion and metastasis encountered in anti-VEGF therapy. This seems to be the case in lung cancer, in which inhibiting HIF-1 activity blocked both cancer growth and metastases in mice.…”

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confidence: 99%

RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

Gillespie

Aguirre

Ravichandran

et al. 2015

JNS

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P atients with the most malignant type of glioma, Grade IV glioblastoma, have a mean survival time of approximately 15 months and an estimated 5-year survival rate of less than 5%.11 High-grade gliomas (Grades III and IV) are the most common primary brain tumors in adults and the fourth leading cause of cancerrelated death. 40 Tumor hypoxia is thought to play an important role in glioblastoma tumor pathobiology by proabbreviatioNs CA-IX = carbonic anhydrase-IX; CED = convection-enhanced delivery; DAB = 3,3′-diaminobenzidine tetrahydrochloride; DCA = dichloroacetate; EHCO = 1-(aminoethyl)iminobis [N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide]; GFP = green fluorescent protein; GLUT-1 = glucose transporter 1; HIF-1a = hypoxia-inducible factor 1a; IHC = immunohistochemistry; MVD = microvascular density; PEG = polyethylene glycol; PI = proliferation index; RNAi = RNA interference; siRNA = small interfering RNA; VEGF = vascular endothelial growth factor. obJeCt High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1a (HIF-1a) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. MetHoDs Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1a in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(amino ethyl)iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convectionenhanced delivery. resUlts Mice receiving daily siRNA injections targeting HIF-1a had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CoNClUsioNs Treating glioblastoma with siRNA targeting HIF-1a in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.

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Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex

Cited by 51 publications

References 79 publications

Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics

RNA interference targeting hypoxia-inducible factor 1α via a novel multifunctional surfactant attenuates glioma growth in an intracranial mouse model

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