Synthesis of Diverse Lactam Carboxamides Leading to the Discovery of a New Transcription‐Factor Inhibitor

Ng, Pui Yee; Tang, Yuchen; Knosp, Wendy M.; Stadler, H. Scott; Shaw, Jared T.

doi:10.1002/anie.200700762

Cited by 73 publications

(51 citation statements)

References 44 publications

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“…Signifi cantly, this includes hits against so-called ' undruggable ' targets and processes, which have traditionally been seen as diffi cult or even impossible to modulate with small molecules. Molecules capable of modulating protein -protein interactions 66 -68 , transcription factor activity 69,70 and multidrug resistance in pathogens 55,71 have all been discovered through the use of DOS libraries. Some examples are shown in Figure 8 .…”

Section: Biological Activitymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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Biologically active molecules can be identifi ed through the screening of small-molecule libraries. Defi ciencies in current compound collections are evidenced by the continuing decline in drugdiscovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an effi cient manner. Recent years have witnessed signifi cant achievements in the fi eld, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.S mall molecular mass chemical entities (so-called small molecules) have always been of interest in chemistry and biology because of their ability to exert powerful eff ects on the functions of macromolecules that comprise living systems 1 -3 . Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry (wherein molecules are sought to chemically modify disease states) and chemical genetics (wherein molecules are used as ' probes ' to study biological systems 3 -8 . Such chemical modulators are most commonly identifi ed by screening collections or ' libraries ' of small molecules. However, a crucial consideration is what compounds to use 3,9,10 . A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration. Th e effi cient creation of functionally diverse small-molecule collections presents a formidable challenge.Traditionally, when a specifi c biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3,9,11 . Th e selection criteria are dramatically complicated if the subsequent screening is ' unbiased ' ; that is, when the precise nature of the biological target is unknown (for example, in a random drug-discovery screen) 4,3,12 . In such situations, the structural features required in the small molecules cannot be defi ned a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specifi c biological target (or family of related targets) is not logical, whereas the random screening of many such ' focused ' collections can be extremely time and cost demanding.In general, the identifi cation of biologically active small molecules may be aided by screening functionally diverse compound libraries (that is, libraries that display a broad range of biological activities), as it has been argued that a greater sample of the bioactive chemical universe (that is, of all bioactive molecules) increases the chance of identifying a compound with the desired properties 3,10,13,14 . As a corollary, ...

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Section: Biological Activitymentioning

confidence: 99%

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

2010

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“…The same is true of non-natural compounds produced using diversity-oriented synthesis and subsequently identified as small-molecule probes of protein-DNA interactions 10 , proteinprotein interactions 11 , transcription-factor activity 12 , multi-drug resistance in pathogens 13 and many other processes often imagined to be impervious to modulation by small molecules. These results suggest that Morton and colleagues' synthetic pathway might also yield molecular probes of many aspects of disease.…”

Section: Years Agomentioning

confidence: 95%

Molecular diversity by design

Schreiber¹

2009

Nature

283

148

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“…As mentioned above, targeting the transcription factor-DNA interaction remains difficult but of high importance; therefore, a number of molecules with high complexity were designed to inhibit general transcription factors. An inhibitor of the HOXA13-DNA interaction was identified via a high-throughput screen of a library of lactam carboxamides (Ng et al, 2007). Researchers utilized a fluorescence polarization assay to screen the compounds and identified two lactam carboxamides which disrupted the HOXA13-DNA interaction.…”

Section: Direct Inhibition Of Hoxa13-dna Interactionmentioning

confidence: 99%

“…One identified inhibitor was further analyzed and demonstrated an IC 50 value of ~6.5 µM. In addition, using a gene reporter assay, which places the HOXA13 transcription factor in control of the expression of luciferase, researchers demonstrated an increase in luciferase experssion following the addition of the HOXA13 inhibitor (Ng et al, 2007). Although the data presented suggest the disruption of the HOXA13-DNA interaction, there is very little additional information regarding this inhibitor.…”

Section: Direct Inhibition Of Hoxa13-dna Interactionmentioning

confidence: 99%