Discovery of an in Vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP

Liu, Feng; Baršytė-Lovejoy, Dalia; Li, Fengling; Xiong, Yan; Korboukh, Victoria K.; Huang, Xi Ping; Allali-Hassani, Abdellah; Janzen, William P.; Roth, Bryan L.; Frye, Stephen V.; Arrowsmith, C.H.; Brown, Peter J.; Vedadi, Masoud; Jin, Jian

doi:10.1021/jm401480r

Cited by 237 publications

(283 citation statements)

References 62 publications

Supporting

Mentioning

273

Contrasting

Order By: Relevance

“…36 Although poor in vivo pharmacokinetic properties of UNC0638 may preclude its use as a drug, additional G9a targeting compounds are being developed, including UNC0642, with similar inhibitory properties and improved in vivo stability. 37 In addition to the identification and development of UNC0638-related compounds, recognition of the role of H3K9 methylation in globin gene regulation could advance mechanistic studies of existing or alternate drugs that augment HbF expression, including cytidine derivatives. Although 5-Aza-29-deoxycytidine is thought to act primarily via DNA demethylation, its epigenetic effects include strong reduction of H3K9me2 histone marks at gene promoters.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Krivega¹,

Byrnes

Vasconcellos

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Krivega¹,

Byrnes

Vasconcellos

et al. 2015

Blood

View full text Add to dashboard Cite

show abstract

“…1B; ref. 72). The uses of UNC-0642 in xenograft tumor models will allow further investigation on the impact of G9a inhibition in CSCs versus non-stem cancer cells, which will give insights into the CSC-specific aspect of such a mechanism.…”

Section: G9a/glp Histone Lysine Methyltransferase Complexes Affect Wnmentioning

confidence: 99%

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Benoit

Guezguez

Boyd

et al. 2014

Clinical Cancer Research

View full text Add to dashboard Cite

Aberrant regulation of the canonical Wnt signaling pathway (Wnt-b-catenin-GSK3 axis) has been a prevalent theme in cancer biology since earlier observations until recent genetic discoveries gleaned from tumor genome sequencing. During the last few decades, a large body of work demonstrated the involvement of the Wnt-b-catenin-GSK3 signaling axis in the formation and maintenance of cancer stem cells (CSC) responsible for tumor growth in several types of human malignancies. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment on how embryonic and normal tissue stem cells are dysregulated in cancer to give rise to CSCs, and how canonical Wnt signaling might be involved. Here, we review emerging concepts highlighting the critical role of epigenetics in CSC development through abnormal canonical Wnt signaling. Finally, we refer to the characterization of novel and powerful inhibitors of chromatin organization machinery that, in turn, restore the Wnt-b-catenin-GSK3 signaling axis in malignant cells, and describe attempts/relevance to bring these compounds into preclinical and clinical studies.

show abstract

“…21 Installing an imidazole (18,IC 50 : 754 nM) reinforced the notion that a basic nitrogen would be critical for effective enzyme inhibition. Substitution of fluorine on the pyrrolidine ring of 12 was evaluated next, with R-and S-fluoro-pyrrolidines 19 and 20 exhibiting robust potency with a slight preference of one enantiomer (19,IC 50 : 3.7 nM) over the other (20,IC 50 : 18 nM). Finally, replacing the cyclobutyl subunit with a geminal dimethyl group (21, R 1 = Me) yielded a slight potency boost (IC 50 : 0.9 nM).…”

mentioning

confidence: 99%

Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a

Sweis

Pliushchev

Brown

et al. 2014

ACS Med. Chem. Lett.

Self Cite

165

141

View full text Add to dashboard Cite

G9a is a histone lysine methyltransferase responsible for the methylation of histone H3 lysine 9. The discovery of A-366 arose from a unique diversity screening hit, which was optimized by incorporation of a propyl-pyrrolidine subunit to occupy the enzyme lysine channel. A-366 is a potent inhibitor of G9a (IC 50 : 3.3 nM) with greater than 1000-fold selectivity over 21 other methyltransferases.KEYWORDS: G9a, methyltransferase, A-366, methylation, epigenetics H istone methyltransferases (HMTs), a class of enzymatic "writers" of epigenetic marks, have recently emerged as targets of potential therapeutic value.1,2 They catalyze the methylation of histone lysines and arginines utilizing Sadenosyl-methionine (SAM) as the cofactor/methyl-source. This process can result in either the activation or repression of transcription.3,4 Dysregulation of methylation at specific histone sites (alterations in the "histone code") has been implicated in many cancers.5−7 Hence, targeting HMT activity has been the subject of much investigation in the field of oncology, even recently reaching human clinical trials. 8 Euchromatic histone methyltransferase 2 (EHMT2), also known as G9a, is an HMT that is primarily responsible for the dimethylation of lysine 9 on histone H3 (H3K9). Several reports have highlighted its link to a variety of cancers. It is upregulated in hepatocellular carcinoma, 9 B cell acute lymphoblastic leukemia, 10 and lung cancers. 11 In addition, elevated expression of G9a in aggressive lung cancer correlates with poor prognosis, while its knockdown in highly invasive lung cancer cells suppressed metastasis in an in vivo mouse model. 12 In prostate cancer cells (PC3), G9a knockdown caused significant morphological changes and inhibition of cell growth. 13While small molecule inhibitors of G9a (Figure 1) have been reported as early as 2005, 14 BIX01294 (1) was the first reported potent and selective inhibitor. 15 It was found to reduce H3K9 dimethyl levels in cells and notably was not a SAM-competitive inhibitor. Recently, a second G9a inhibitor, UNC0638 (2), was disclosed. Quinazoline 2, which incorporated a lysine-mimic via an n-propyl-pyrrolidine exhibited a >10-fold enhancement in potency over 1 along with selectivity over a panel of 17 other epigenetic targets. 16−19 Our efforts toward the identification of chemically distinct G9a inhibitors commenced with a chemical diversity subset screen of our compound collection. The assay format employed was a peptide-based AlphaLISA, measuring the levels of H3K9 dimethylation. Several clusters of related chemical matter were identified, but a singleton stood out: spiro[cyclobutane-1,3′-indol]-2′-amine (3) as having robust potency (IC 50 : 153 nM). The low molecular weight of this compound translated to a high binding efficiency index (BEI) value of 27. 20 Such a feature rendered 3 as an attractive starting point for chemistry efforts aimed at further potency optimization.The importance of the various subunits of 3 was initially interrogated by evaluation of a ...

show abstract

Discovery of an in Vivo Chemical Probe of the Lysine Methyltransferases G9a and GLP

Cited by 237 publications

References 62 publications

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Inhibition of G9a methyltransferase stimulates fetal hemoglobin production by facilitating LCR/γ-globin looping

Molecular Pathways: Epigenetic Modulation of Wnt–Glycogen Synthase Kinase-3 Signaling to Target Human Cancer Stem Cells

Discovery and Development of Potent and Selective Inhibitors of Histone Methyltransferase G9a

Contact Info

Product

Resources

About