Pharmacological inhibition of the transcription factor PU.1 in leukemia

Antony-Debré, Iléana; Paul, A.; Leite, Joana; Mitchell, Kelly; Kim, Hye Mi; Carvajal, Luis A.; Todorova, Tihomira I.; Huang, Kenneth; Kumar, Arvind; Farahat, Abdelbasset A.; Bartholdy, Boris; Narayanagari, Swathi Rao; Chen, Jiahao; Ambesi-Impiombato, Alberto; Ferrando, Adolfo A.; Mantzaris, Ioannis; Gavathiotis, Evripidis; Verma, Amit; Will, Britta; Boykin, David W.; Poon, Gregory M.K.; Steidl, Ulrich

doi:10.1172/jci92504

Cited by 91 publications

(92 citation statements)

References 57 publications

(60 reference statements)

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“…Disregulation of PU.1 can block hematopoietic cell differentiation and expand a clonal population of leukemic cells, leading to leukemogenesis . It has been reported that in more than 50% of patients with AML, disruption of PU.1 expression or activity is present . While overexpression of PU.1 can lead to apoptosis in AML, elevation of PU.1 levels or activity is difficult to restore pharmacologically .…”

Section: Ets Proteins As Prominent Oncodriversmentioning

confidence: 99%

“…It has been reported that in more than 50% of patients with AML, disruption of PU.1 expression or activity is present . While overexpression of PU.1 can lead to apoptosis in AML, elevation of PU.1 levels or activity is difficult to restore pharmacologically . Interestingly, it has been shown that lowering the PU.1 level further by RNA interference or inhibiting the PU.1 DNA‐binding through small molecule inhibitors that target the DNA minor groove can reduce AML cell growth in vitro and in vivo …”

Section: Ets Proteins As Prominent Oncodriversmentioning

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: Ets Proteins As Prominent Oncodriversmentioning

confidence: 99%

Section: Ets Proteins As Prominent Oncodriversmentioning

confidence: 99%

ETS transcription factors as emerging drug targets in cancer

Hsing

Wang

Rennie

et al. 2019

Medicinal Research Reviews

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“…The heterocyclic diamidine minor groove binders that have been designed and prepared in our group have been demonstrated to get into a variety of cell types and to have clinically useful biological activity with low toxicity . In addition, diamidines have been shown to be excellent inhibitors of transcription factors (TFs) both in vitro and in vivo . The diamidine minor groove binders synthesized previously have been essentially pure AT interacting compounds.…”

Section: Introductionmentioning

confidence: 99%

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

Farahat

Guo

Shoeib

et al. 2020

Chemistry A European J

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A series of small diamidines with thiophene and modified N‐alkylbenzimidazole σ‐hole module represent specific binding to single G⋅C base pair (bp) DNA sequence. The variation of N‐alkyl or aromatic rings were sensitive to microstructures of the DNA minor groove. Thirteen new compounds were synthesized to test their binding affinity and selectivity. The dicyanobenzimidazoles needed to synthesize the target diamidines were made via condensation/cyclization reactions of different aldehydes with different 3‐amino‐4‐(alkyl‐ or phenyl‐amino) benzonitriles. The final diamidines were synthesized using lithium bis‐trimethylsilylamide (LiN[Si(CH3)3]2) or Pinner methods. The newly synthesized compounds showed strong binding and selectivity to AAAGTTT compared to similar sequences AAATTT and AAAGCTTT investigated by several biophysical methods including biosensor‐SPR, fluorescence spectroscopy, DNA thermal melting, ESI‐MS spectrometry, circular dichroism, and molecular dynamics. The binding affinity results determined by fluorescence spectroscopy are in accordance with those obtained by biosensor‐SPR. These small size single G⋅C bp highly specific binders extend the compound database for future biological applications.

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“…Since these non-amide compounds have excellent cell uptake and biological activities, there is a compelling need to develop analogs with broad DNA sequence recognition. [23,24] …”

Section: Introductionmentioning

confidence: 99%

First Structure of a Designed Minor Groove Binding Heterocyclic Cation that Specifically Recognizes Mixed DNA Base Pair Sequences

Harika

Germann

Wilson

2017

Chemistry A European J

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The high-resolution NMR structure of the first heterocyclic, non-amide, organic cation that strongly and selectively recognizes mixed AT/GC bp (bp=base pair) sequences of DNA in a 1:1 complex is described. Compound designs of this type provide essential methods for control of functional, non-genomic DNA sequences and have broad cell uptake capability, based on studies from animals to humans. The high-resolution structural studies described in this report are essential for understanding the molecular basis for the sequence-specific binding as well as for new ideas for additional compound designs for sequence-specific recognition. The molecular features, in this report, explain the mechanism of recognition of both A⋅T and G⋅C bps and are an interesting molecular recognition story. Examination of the experimental structure and the NMR restrained molecular dynamics model suggests that recognition of the G⋅C base pair involves two specific H-bonds. The structure illustrates a wealth of information on different DNA interactions and illustrates an interfacial water molecule that is a key component of the complex.

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Pharmacological inhibition of the transcription factor PU.1 in leukemia

Cited by 91 publications

References 57 publications

ETS transcription factors as emerging drug targets in cancer

ETS transcription factors as emerging drug targets in cancer

Small Sequence‐Sensitive Compounds for Specific Recognition of the G⋅C Base Pair in DNA Minor Groove

First Structure of a Designed Minor Groove Binding Heterocyclic Cation that Specifically Recognizes Mixed DNA Base Pair Sequences

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