PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Inhibition of Histone Demethylases Offers a Novel and Promising Approach for the Treatment of Cancer and Other Diseases Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Inhibitors of Histone Demethylases
Patent Application Number: WO 2015/153498 Al Priority Application: US 61/972,972
Publication date: Priority date:
Inventors:
Labelle, M; Zhang, R.; Martyr, C. D.; Saraswat, N.; Boesen, T.
Assignee Company:
Epitherapeutics, Aps; Ole Maalues Vej 3, DK-2200 Kubenhavn N (DK)
8 October 2015 31 March 2014
For US only: Labelle, M; 10 Melbourne Way, Basking Ridge, New Jersey 07920, USA Disease Area:
Cancer and HDME-dependent proliferative diseases
Summary:
The invention in this patent application relates to heterocyclic aromatic compounds represented generally by formula (I), which
Biological Target:
Histone demethylases (HDMEs)
are capable of modulating the activities of histone demethylases (HDMEs) and may provide useful therapy to treat cancer and other HDME-dependent proliferative diseases. Nuclear DNA is too large to exist as a linear structure; instead, it exists as a condensed, much smaller but more complex and highly ordered structure called chromatin. In addition to DNA, chromatin contains protein and RNA. Chromatin is organized into smaller repeat units called nucleosomes composed of the DNA wrapped around a spool made of octamer of histones. Covalent chemical derivatizations of the chromatin components can cause changes in the ordered chromatin structure. Many reversible chemical modifications occur on the chromatin components that are essential to the functions of chromatin to determine regions of active and silenced transcription. They also have profound effects on the fundamental cellular processes such as differentiation, proliferation, and apoptosis. Chemical modifications such as methylations of DNA and/or histones are part of epigenetic regulations, which include any heritable changes in gene expression other than those mediated at the DNA sequencing level. Histones, the nucleosome core proteins, contain basic amino acid residues such as lysine and arginine. The amino groups on the lysine or arginine residues are subjected to several covalent modifications such as N-methylation, N-acetylation, and N-phosphorylation. These modifications can affect the histone functions based on their nature and location. Histone tails contain numerous lysine sites; a lysine (K) site is identified by its location on a specific histone (H) subunit, for example, H3K4 refers to a lysine residue in the fourth position on histone H3. The methylated sites are further identified by adding me1, me2, or me3 to denote mono-, di-, or trimethyl derivatives. N-Methylations of the histone lysine residues play critical roles in many epigenetic events. The methylation reaction is regulated by histone methyltransferases and functions as a mechanism to regulate DNA transcription. New evidence suggests that site-specific methylations are linked to specific biological processes ranging from transcriptional regulation to epigenetic silencing. Evidence also suggests that histone methylation may provide a stable genomic imprint that may serve to regulate gene expression as well as other epigenetic phenomena. The reverse process, i.e., the demethylation of methylated histones, is regulated by histone demethylases. There are two main classes of histone demethylases: the amine oxidases catalyzed by flavin adenine dinucleotide (FAD) and the dioxygenases catalyzed by Fe(II)/α-ketoglutarate. Studies have shown that methylation and demethylation of a specific H3 lysine residue can be associated with epigenetic marks that define transcriptionally active or inactive chromatin. For example, while methylation of H3K9 is usually associated with epigenetically silenced chromatin, the methylation of H3K4 is associated with transcriptionally active chromatin. Similarly, di- and trimethylation of H3K27 marks are repressive, while the methylation of H3K36 mark is associated with gene activation. Dysregulation of histone methyltransferases and/or demethylases may result in significant changes in histone lysine methylation, which, in turn, may be responsible for the pathogenesis of several diseases including cancer as well as metabolic, inflammatory, neurodegenerative, and cardiovascular diseases. Therefore, selective modulation of aberrant functions of these enzymes may provide an effective treatment for the above diseases.
Special Issue: Epigenetics Received: November 14, 2015 Published: December 01, 2015 r 2015 American Chemical Society
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ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Many studies have demonstrated the potential of histone demethylases as oncogenes including, for example: • Lysine-specific demethylase 4C (KDM4C, a.k.a. JMJD2C) that demethylates the H3K9me3 mark was found to be overexpressed in several human tumors such as squamous cell carcinoma, metastatic lung carcinoma, prostate cancer, breast cancer, and several others. • The histone demethylase KDM4A (JMJD2A) that erases the H3K9 mark has also been shown to be overexpressed in prostate cancer. • Lysine-specific demethylase 5B (KDM5B; a.k.a. JARID1B) demethylates the H3K4me3 mark. It is believed that this function leads to repressing of tumor repressor genes and subsequently decreases transcriptional activation in the affected chromatin regions. The enzyme is overexpressed in prostate cancer, and it is also associated with malignancy and poor prognosis. • Lysine-specific demethylase 5A (KDM5A; a.k.a. JARID1A) that erases the H3K4me2 and H3K4me3 marks is overexpressed in gastric cancer, and its gene is amplified in cervix carcinoma. • Lysine-specific demethylase 2B (KDM2B; a.k.a. JHDM1B) erases the H3K36me2 mark and has been shown to be highly expressed in human cancers. It demethylates H3K36me2 on the tumor-suppressor gene Ink4b (pl5Ink4b). This activity is linked to silencing the expression of this senescence-mediating gene in mouse embryonic fibroblasts (MEFs) and in leukemic cells. These data indicate that the inhibition of the lysine-specific demethylases, particularly those identified as potential oncogenes, is a viable therapeutic target for the treatment of HDME-dependent diseases such as cancer. Cancer continues to be a devastating disease that affects millions of people worldwide, and there is a great need for the development of new effective and specific treatments for this disease. Inhibition of HDMEs is a novel approach for the treatment of cancers and other proliferative diseases. The compounds disclosed in this patent application are HDME inhibitors capable of modulating the activities of histone demethylases and may therefore provide needed effective treatments for cancer. Important Compound Classes:
Key Structures:
The inventors listed the structures of 108 examples of formula (I) including the following compounds:
Biological Assay:
The compounds of the invention were tested using the following assays: • Histone Lysine Demethylase AlphaLISA Assays for IC50 value determination • Cell Assays for IC50 value determination • Histone Lysine Demethylase Immunofluorescence Assays for IC50 value determination • Cell Proliferation Assays for EC50 value determination
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dx.doi.org/10.1021/acsmedchemlett.5b00437 |ACS Med. Chem. Lett. 2016, 7, 128–130
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
Biological Data:
The biological data obtained from testing the above representative examples are listed in the following table:
Recent Review Articles:
Key: +++, IC50 < 250 nM; ++, 250 nM < IC50 < 2500 nM; +, IC50 > 2500 nM 1. Bauge, C.; Bazille, C.; Girard, N.; Lhuissier, E.; Boumediene, K. Fut. Med. Chem. 2014, 6 (17), 1943 1965. 2. Wang, Z.; Patel, D. J. Q. Rev. Biophys. 2013, 46 (4), 349 373. 3. Hojfeldt, J. W.; Agger, K.; Helin, K. Nat. Rev. Drug Discovery 2013, 12 (12), 917 930. 4. Helin, K.; Dhanak, D. Nature 2013, 502 (7472), 480 488.
’ AUTHOR INFORMATION Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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