Perspectives on the Discovery of Small-Molecule Modulators for Epigenetic Processes

Lu, Quinn; Quinn, Amy; Patel, Mehul; Semus, Simon F.; Graves, Alan P.; Bandyopadhyay, Deepak; Pope, Andrew J.; Thrall, Sara H.

doi:10.1177/1087057112437763

Cited by 21 publications

(13 citation statements)

References 147 publications

(184 reference statements)

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“…One of the major challenges of phenotypic screening is the identification of the target(s) of a hit molecule, (i.e. target deconvolution) and the elucidation of the mode of action [21–23]. Nonetheless, phenotypic screening is valuable for identifying hit compounds for complex processes, such as epigenetic modulation [21].…”

Section: Drug Repurposingmentioning

confidence: 99%

Shifting from the single to the multitarget paradigm in drug discovery

Medina-Franco

Giulianotti

Welmaker

et al. 2013

Drug Discovery Today

409

246

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Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and highthroughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target–one drug model to a multiple-target approach. Furthermore, the goals of lead identification are being expanded accordingly to identify not only ‘key’ compounds that fit with a single-target ‘lock’, but also ‘master key’ compounds that favorably interact with multiple targets (i.e. operate a set of desired locks to gain access to the expected clinical effects).

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Section: Drug Repurposingmentioning

confidence: 99%

Shifting from the single to the multitarget paradigm in drug discovery

Medina-Franco

Giulianotti

Welmaker

et al. 2013

Drug Discovery Today

409

246

View full text Add to dashboard Cite

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“…However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates 3 , including cyclin-dependent kinases (CDKs) 4 . Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7.…”

mentioning

confidence: 99%

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Kwiatkowski

Zhang

Rahl

et al. 2014

Nature

740

937

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Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state 1 , but direct pharmacological inhibition of transcription factors has thus far proven difficult 2 . However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates 3 , including cyclin-dependent kinases (CDKs) 4 . Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state.

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“…6 Inhibition of histone lysine methyltransferases such as EZH2 can decrease the level of H3K27me3; thus, these methyltransferases constitute a novel class of drug target for cancer therapeutics. 9 A recent study supported this concept by reporting that a small-molecule EZH2 inhibitor, GSK126, may provide a treatment option for EZH2 mutant lymphoma. 10 Multiple biochemical assays have been reported in the drug discovery effort for small-molecule inhibitors against different epigenetic enzymes.…”

Section: Introductionmentioning

confidence: 66%

Development of Multiple Cell-Based Assays for the Detection of Histone H3 Lys27 Trimethylation (H3K27me3)

Qian

Lü

et al. 2013

ASSAY and Drug Development Technologies

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Posttranslational modification of histone proteins in eukaryotes plays an important role in gene transcription and chromatin structure. Dysregulation of the enzymes involved in histone modification has been linked to many cancer forms, making this target class a potential new area for therapeutics. A reliable assay to monitor small-molecule inhibition of various epigenetic enzymes should play a critical role in drug discovery to fight cancer. However, it has been challenging to develop cell-based assays for high-throughput screening (HTS) and compound profiling. Recently, two homogeneous cell-based assay kits using the AlphaLISA Ò and LanthaScreen Ò technologies to detect trimethyl histone H3 Lysine 27 have become commercially available, and a heterogeneous cell assay with modified dissociation-enhanced lanthanide fluorescence immunoassay (DELFIA Ò ) format has been reported. To compare their pros and cons, we evaluated, optimized, and validated these three assay formats in three different cell lines and compared their activities with traditional Western blot detection of histone methylation inhibition by using commercial and in-house small-molecule inhibitors. Our data indicate that, although all four formats produced acceptable results, the homogeneous AlphaLISA assay was best suited for HTS and compound profiling due to its wider window and ease of automation. The DELFIA and Western blot assays were useful as validation tools to confirm the cell activities and eliminate potential false-positive compounds.

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Perspectives on the Discovery of Small-Molecule Modulators for Epigenetic Processes

Cited by 21 publications

References 147 publications

Shifting from the single to the multitarget paradigm in drug discovery

Shifting from the single to the multitarget paradigm in drug discovery

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor

Development of Multiple Cell-Based Assays for the Detection of Histone H3 Lys27 Trimethylation (H3K27me3)

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