2015
DOI: 10.1021/jm501436m
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Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

Abstract: WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine–piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant… Show more

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Cited by 70 publications
(86 citation statements)
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“…Compound 3 binds in a twisted conformation, as previously described for 1, with the indazole substituent at C5 of the pyridine ring forming a pi-cation interaction with Arg356 (Figure 1B) (Mallinger et al, 2015, 2016a). Compound 4 forms similar interactions with the hinge region and with the catalytic Lys52 to those observed for compound 3, and its p -chlorophenyl substituent occupies the same region as the indazole subsituent of compound 3; however, the scaffold architecture of the two compounds is entirely different (Figure 1B).…”
Section: Resultsmentioning
confidence: 52%
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“…Compound 3 binds in a twisted conformation, as previously described for 1, with the indazole substituent at C5 of the pyridine ring forming a pi-cation interaction with Arg356 (Figure 1B) (Mallinger et al, 2015, 2016a). Compound 4 forms similar interactions with the hinge region and with the catalytic Lys52 to those observed for compound 3, and its p -chlorophenyl substituent occupies the same region as the indazole subsituent of compound 3; however, the scaffold architecture of the two compounds is entirely different (Figure 1B).…”
Section: Resultsmentioning
confidence: 52%
“…All four compounds had single digit nanomolar binding affinities for CDK8 and 19, and were very highly selective with little evidence for off-target activity in extended protein kinase panels (Figure 1—source data 1). Our compounds also potently inhibited inducible (7dF3; Ewan et al, 2010) or basal (LS174T; Dale et al, 2015; Mallinger et al, 2015) WNT-pathway luciferase-reporter expression together with STAT1 SER727 phosphorylation ‑ a target-engagement biomarker ‑ at low nanomolar concentrations (Figure 1A and Figure 1—source data 1) (Bancerek et al, 2013; Dale et al, 2015).
10.7554/eLife.20722.003Figure 1.Optimised compounds for exploring CDK8 and CDK19 function.( A ) Chemical structure and activity of compounds 2, 3 and 4 (n > 2, mean ± s.d.).
…”
Section: Resultsmentioning
confidence: 89%
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“…Despite the obvious importance of Mediator in gene expression control, little is known about shared and unique functions of the CDK-module paralogs. Recently, a number of dual inhibitors of CDK8 and CDK19 have been developed, including Cortistatin A, Senexin A, CCT251921 and MSC2530818 (Cee et al, 2009; Clarke et al, 2016; Czodrowski et al, 2016; Dale et al, 2015; Koehler et al, 2016; Mallinger et al, 2015; Mallinger et al, 2016a; Mallinger et al, 2016b; Porter et al, 2012; Schiemann et al, 2016). While many of these compounds appear to have efficacy against cancer cell lines in vitro , it remains unclear whether the effects are due to inhibition of CDK8, CDK19 or both.…”
Section: Introductionmentioning
confidence: 99%
“…The loss of function of the APC protein impairs b-catenin phosphorylation, and this substance, accumulated in the cell nucleus, potentiates the expression of the genes stimulating the proliferation processes [41]. Currently there are attempts made at inhibiting this pathway with the use of the available therapeutic agents, yet no efficient inhibitors have been found.…”
Section: Wnt Pathway (Iib)mentioning
confidence: 99%