Patent Highlight Cite This: ACS Med. Chem. Lett. XXXX, XXX, XXX-XXX
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Lysine-Specific Demethylase 1 (LSD1) Inhibitors as Potential Treatment for Different Types of Cancers Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India Patent Application Title:
Cyano-Substituted Indole Compounds and Uses Thereof as LSD1 Inhibitors
Patent Application Number:
WO 2017/149463 A1
Publication date:
8 September 2017
Priority Application:
PCT/CN2016/075195
Priority date:
1 March 2016
Inventors:
Du-Cuny, L.; Xiao, Q.; Xun, G.; Zheng, Q.
Applicants:
Novartis AG [CH/CH]; Lichtstrasse 35, 4056 Basel (CH)
Disease Area:
LSD1-mediated diseases and disorders such as different types of cancers
Biological Target:
Lysine-specific demethylase 1A (LSD1)
Summary:
The invention in this patent application relates to 5-cyano indole derivatives represented generally by formula I. These compound are lysine-specific demethylase 1 (LSD1) inhibitors and may be useful for the treatment of LSD1-mediated diseases or disorders including, but are not limited to, B cell lymphoma, acute myeloid leukemia, gastric cancer, hepatocellular carcinoma, prostate cancer, breast carcinoma, neuroblastoma, glioblastoma, nasopharyngeal carcinoma, colon cancer, gallbladder cancer, esophageal cancer, head and neck cancer, lung cancer, ovarian cancer, pancreatic cancer, endometrial carcinoma, and soft tissue sarcomas such as rhabdomyosarcoma (RMS), chondrosarcoma, osteosarcoma, Ewing’s sarcoma, liver fibrosis, and sickle cell disease. One of the major pathways that regulate gene expression is the post-translational chemical modification of the chromatin structure via methylation and acetylation of the side chain amino groups of the lysine (K) residues of histones. These modifications are important factors that determine the organization as well as the formation of active and inactive regions of the genome. Researchers have discovered several enzymes that regulate histone modifications and identified them as potential therapeutic targets to design novel treatments for several diseases and disorders due to their effects on gene expression and cellular function. Regarding the methylation of histones, there are several enzymes known as lysine methyltransferases that catalyze the N-methylation and others known as lysine demethylases that catalyze the N-demethylation of specific lysine residues within the histones. Histone methylation was believed to be an irreversible process until the discovery of the first known demethylating enzyme, the lysine-specific demethylase 1 (LSD1 or KDM1A) in 2004. Since then, researchers have identified and characterized additional histone demethylases. These demethylases were classified into two subgroups based on their catalytic mechanisms. One subgroup includes LSD1 and lysine-specific demethylase 2 (LSD2); these enzymes use flavin adenine dinucleotide (FAD) as a cofactor to oxidatively cleave mono- and di- (but not tri-) methylated amines on lysine residues of histone H3. Another subgroup was found to contain the Jumonji C (JmjC) domain, which utilizes Fe(II) cation and 2-oxoglutarate-dependent dioxygenases for the oxidative cleavage of mono-, di-, and trimethylated amines on lysine residues of histones. LSD1 contains three major domains:
• • •
the N-terminal Swi3-Rsc8-Moira (SWIRM) domain, which functions in nucleosome targeting the tower domain, which participates in protein−protein interactions the C-terminal catalytic domain, which has structural similarity to the monoamine oxidases
LSD1 shares homology with LSD2 but shows distinct differences from the JmjC type histone demethylases. The enzymatic activity of LSD1 is dependent on the redox process of FAD. The reaction mechanism requires protonation of the nitrogen to be demethylated, and that limits its demethylating abilities to mono- and dimethylated lysine residues. Specifically, LSD1 targets the methylated histones in position 4 or 9 of histone H3 (i.e., H3K4 and H3K9). LSD1 also targets several other nonhistone substrates including p53, E2F1, DNMT1, and STAT3. Studies have shown that LSD1 is involved in cell proliferation, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Dysfunction in the activities of LSD1 is believed to be responsible for a number of myeloproliferative and lymphoproliferative diseases such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). It has also been linked to the aberrant function of the androgen receptor in prostate cancer and small cell lung cancer. Therefore, inhibition of LSD1 has become an attractive therapeutic target to discover novel anticancer treatments. Researchers have identified many reversible and irreversible LSD1 inhibitors that may potentially be used as treatment for cancer. LSD1 is structurally similar to the Flavin-dependent monoamine oxidases (MAOs). Both LSD1 and MAOs utilize flavin adenine dinucleotide (FAD) as cofactor, Thus, a number of known MAO inhibitors have been shown to also inhibit LSD1 through irreversible interaction of FAD. Attempts have also been made to discover reversible inhibitors of LSD1. Therefore, the inhibition of LSD1 provides a promising pharmacological target to design novel treatments for cancer and other disorders that associate with LSD1’s activity. In particular, the need exists for novel small molecules that inhibit the activity of LSD1, such as the compounds of formula I of this patent application, which includes both irreversible and reversible inhibitors of LSD1.
Received: October 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00426 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
ACS Medicinal Chemistry Letters
Patent Highlight
Important Compound Classes:
Key Structures:
The inventors described the synthesis and structures of 101 examples of formula I compounds including the following representative examples:
Biological Assay:
The following assays were used to test the compounds of formula I:
1. 2. 3. 4. 5. 6.
FL-LSD1 LC-MS assay CD11b FACS assay CD11b qPCR assay Target region ChiP-qPCR assay Antiproliferation assay in Molm13 cell Anticolony formation assay in Molm13 cell
Biological Data:
The IC50 values from assays 1 and 5 obtained from testing the above representative examples are listed in the following table:
Recent Review Articles:
1. Ambrosio, S.; Sacca, C. D.; Majello, B. BBA, Gene Regul. Mech. 2017, 1860 (9), 905−910. 2. Przespolewski, A.; Wang, E. S. Expert Opin. Investig. Drugs 2016, 25 (7), 771−780.
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3. Zheng, Y.-C.; Ma, J.; Wang, Z.; Li, J.; Jiang, B.; Zhou, W.; Shi, X.; Wang, X.; Zhao, W.; Liu, H.-M. Med. Res. Rev. 2015, 35 (5), 1032−1071.
AUTHOR INFORMATION
Corresponding Author
*Address: 1383 Jasper Drive, Ambler, Pennsylvania 19002, United States. Tel: 215-913-7202. E-mail:
[email protected]. Notes
The author declares no competing financial interest.
B
DOI: 10.1021/acsmedchemlett.7b00426 ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX
