Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL

Jacob, Nicholas T.; Lockner, Jonathan W.; Kravchenko, Vladimir V.; Janda, Kim D.

doi:10.1002/anie.201402133

Cited by 32 publications

(40 citation statements)

References 17 publications

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“…In parallel to investigating this disparity, Jacob et al . recently reported a series of NMR and X-ray crystallography studies that determined the chemical structure of ONC201/NSC350625 obtained from the NCI to be an angular [3,4-e] isomer of the structure reported in the original disclosure by Stahle et al and subsequent disclosures of the molecule by the NCI and Allen et al [ 8 ]. This angular [3,4-e] isomer has the imidazo ring fused at an angle to the axis of the pyridopyrimidine rings.…”

Section: Introductionmentioning

confidence: 99%

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

et al. 2014

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We previously identified TRAIL-inducing compound 10 (TIC10), also known as NSC350625 or ONC201, from a NCI chemical library screen as a small molecule that has potent anti-tumor efficacy and a benign safety profile in preclinical cancer models. The chemical structure that was originally published by Stahle, et. al. in the patent literature was described as an imidazo[1,2-a]pyrido[4,3-d]pyrimidine derivative. The NCI and others generally accepted this as the correct structure, which was consistent with the mass spectrometry analysis outlined in the publication by Allen et. al. that first reported the molecule's anticancer properties. A recent publication demonstrated that the chemical structure of ONC201 material from the NCI is an angular [3,4-e] isomer of the originally disclosed, linear [4,3-d] structure. Here we confirm by NMR and X-ray structural analysis of the dihydrochloride salt form that the ONC201 material produced by Oncoceutics is the angular [3,4-e] structure and not the linear structure originally depicted in the patent literature and by the NCI. Similarly, in accordance with our biological evaluation, the previously disclosed anti-cancer activity is associated with the angular structure and not the linear isomer. Together these studies confirm that ONC201, produced by Oncoceutics or obtained from the NCI, possesses an angular [3,4-e] structure that represents the highly active anti-cancer compound utilized in prior preclinical studies and now entering clinical trials in advanced cancers.

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Section: Introductionmentioning

confidence: 99%

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

et al. 2014

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“…S1–S5). 24–26 We note the structure of compound 1a allows for tautomerization. Ab initio calculations (B3LYP/6-31G ⁄⁄ ; gas-phase) predict compound 1a exists primarily in the tautomeric form depicted throughout this text.…”

mentioning

confidence: 97%

Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2 H -pyrrol-2-one actives verified by ALARM NMR

Dahlin

Nissink

Francis

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Despite its wide use, not every high-throughput screen (HTS) yields chemical matter suitable for drug development campaigns, and seldom are ‘go/no-go’ decisions in drug discovery described in detail. This case report describes the follow-up of a 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one active from a cell-free HTS to identify small-molecule inhibitors of Rtt109-catalyzed histone acetylation. While this compound and structural analogs inhibited Rtt109-catalyzed histone acetylation in vitro, further work on this series was halted after several risk mitigation strategies were performed. Compounds with this chemotype had a poor structure–activity relationship, exhibited poor selectivity among other histone acetyltransferases, and tested positive in a β-lactamase counter-screen for chemical aggregates. Furthermore, ALARM NMR demonstrated compounds with this chemotype grossly perturbed the conformation of the La protein. In retrospect, this chemotype was flagged as a ‘frequent hitter’ in an analysis of a large corporate screening deck, yet similar compounds have been published as screening actives or chemical probes versus unrelated biological targets. This report—including the decision-making process behind the ‘no-go’ decision—should be informative for groups engaged in post-HTS triage and highlight the importance of considering physicochemical properties in early drug discovery.

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“…6D). To confirm that TNFSF10 eRNA KD is specific for limiting the virusinduced apoptosis, we induced TNFSF10 expression by a distinct mechanism using TIC10, a small molecule inducer of FOXO3 that activates the TNFSF10 promoter (Jacob et al 2014). Thus, TIC10 treatment would result in apoptosis via a distinct mechanism, compared to viral infection-induced apoptosis.…”

Section: Multiple Ernas Collaborate In Regulating Target Gene Transcrmentioning

confidence: 97%

Global transcriptional activity dynamics reveal functional enhancer RNAs

et al. 2018

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Active enhancers of the human genome generate long noncoding transcripts known as enhancer RNAs (eRNAs). How dynamic transcriptional changes of eRNAs are physically and functionally linked with target gene transcription remains unclear. To investigate the dynamic functional relationships among eRNAs and target promoters, we obtained a dense time series of GRO-seq and ChIP-seq data to generate a time-resolved enhancer activity map of a cell undergoing an innate antiviral immune response. Dynamic changes in eRNA and pre-mRNA transcription activities suggest distinct regulatory roles of enhancers. Using a criterion based on proximity and transcriptional inducibility, we identified 123 highly confident pairs of virus-inducible enhancers and their target genes. These enhancers interact with their target promoters transiently and concurrently at the peak of gene activation. Accordingly, their physical disassociation from the promoters is likely involved in post-induction repression. Functional assessments further establish that these eRNAs are necessary for full induction of the target genes and that a complement of inducible eRNAs functions together to achieve full activation. Lastly, we demonstrate the potential for eRNA-targeted transcriptional reprogramming through targeted reduction of eRNAs for a clinically relevant gene, TNFSF10, resulting in a selective control of interferon-induced apoptosis.

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Pharmacophore Reassignment for Induction of the Immunosurveillance Cytokine TRAIL

Cited by 32 publications

References 17 publications

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity

Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2 H -pyrrol-2-one actives verified by ALARM NMR

Global transcriptional activity dynamics reveal functional enhancer RNAs

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