Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Liang, Jun; Zhang, Birong; Labadie, Sharada S.; Ortwine, Daniel F.; Vinogradova, Maia; Kiefer, James R.; Gehling, Victor S.; Harmange, Jean-Christophe; Cummings, Richard; Lai, Tommy; Liao, Jiangpeng; Zheng, Xiaoping; Liu, Yichin; Gustafson, Amy; Porten, Erica Van der; Mao, Weifeng; Liederer, Bianca M.; Deshmukh, Gauri; Classon, Marie; Trojer, Patrick; Dragovich, Peter S.; Murray, Lesley J.

doi:10.1016/j.bmcl.2016.06.078

Cited by 47 publications

(33 citation statements)

References 17 publications

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“…We found that inhibition of KDM5 increased cellular sensitivity to fulvestrant in all cell lines tested except in T-47D cells (Figure 1B). To validate these findings in vivo , we performed xenograft assays using MCF7 cells and C48, a KDM5i suitable for in vivo use (Liang et al, 2016). We first confirmed that C48 also increased cellular sensitivity to fulvestrant in cell culture (Fig.…”

Section: Resultsmentioning

confidence: 99%

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

et al. 2018

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SUMMARY Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+ breast tumors. Single cell RNA-seq, cellular barcoding, and mathematical modeling demonstrate that endocrine-resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor-resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.

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Section: Resultsmentioning

confidence: 99%

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

et al. 2018

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“…All these limitations hamper the use of these molecules as tool compounds in a cellular context. Among the others, a recently reported KDM5A inhibitor (Liang et al., 2016) is the most remarkable tool compound/pre-clinical candidate for cancer therapy. This orally bioavailable pyrazolopyrimidinone shows both high inhibitions of KDM5 demethylases on a TR-FRET biochemical assay and good activity in cell-based assays, thus making this compound the best chemical tool reported in the literature to date.…”

Section: Introductionmentioning

confidence: 99%

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Tumber

Nuzzi

Hookway

et al. 2017

Cell Chemical Biology

118

102

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SummaryMethylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.

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“…However, these compounds have shown a lack of selectivity between the KDM4 and KDM5 families. Recently, an orally bioavailable pyrazolopyrimidinone KDM5A inhibitor has been reported that has shown high inhibitions of KDM5 demethylases on a TR‐FRET biochemical assay. Moreover, also cell‐based assay reported good activity in PC9 by measuring H3K4Me3 level.…”

Section: Kdm5 Inhibitors In Anticancer Therapymentioning

confidence: 99%

KDM5 demethylases and their role in cancer cell chemoresistance

Plch

Hraběta

Eckschlager

2018

Intl Journal of Cancer

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Histone methylation is important in the regulation of genes expression, and thus its dysregulation has been observed in various cancers. KDM5 enzymes are capable of removing tri‐ and di‐ methyl marks from lysine 4 on histone H3 (H3K4) which makes them potential players in the downregulation of tumor suppressors, but could also suggest that their activity repress oncogenes. Depending on the methylation site, their effect on transcription can be either activating or repressing. There is emerging evidence for deregulation of KDM5A/B/C/D and important phenotypic consequences in various types of cancer. It has been suggested that the KDM5 family of demethylases plays a role in the appearance of drug tolerance. Drug resistance remains a challenge to successful cancer treatment. This review summarizes recent advances in understanding the functions of KDM5 histone demethylases in cancer chemoresistance and potential therapeutic targeting of these enzymes, which seems to prevent the emergence of a drug‐resistant population.

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Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Cited by 47 publications

References 17 publications

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

KDM5 demethylases and their role in cancer cell chemoresistance

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