Inhibitors of Enhancer of Zeste Homologue 2 (EZH2) as Treatment for Cancer, Autoimmune, and Other Diseases

Abstract

The invention in this patent application relates to 2-amino-7-aza-quinoline derivatives represented herein by formula 1. These compounds are inhibitors of the enhancer of zeste homologue 2 (EZH2), and may potentially provide useful treatment for a disease or condition mediated by EZH2 and PRC2-EZH2 complex such as breast cancer, prostate cancer, hepatocellular carcinoma and possibly other cancers.

Important Compound Classes

Title

Aza-Quinoline Compounds and Uses Thereof. https://patents.google.com/patent/US20260076968A1/en?oq=US+2026%2f0076968+Al

Patent Publication Number

US 2026/0076968 Al

Publication Date

March 19, 2026

Priority Application

PCT/CN2019/108296

Priority Date

September 26, 2019

Inventors

Li, L.; Dai, X.; Dore, M.; Gu, X.-J. J.; Liu, K. C.; Mak, S. Y. F.; Mi, Y.; Oyang, C.; Papillon, J.; Qi, W. (V.); Yan, X.; Yu, Z.; Zhang, J. Y. (J.); Zhao, K.

Assignee Company

Novartis AG, Basel (CH)

Disease Area

Cancer, autoimmune diseases and related disorders

Biological Target

EZH2 and/or PRC2-EZH2 complex

Summary

Histones are small proteins structurally characterized by being abundant in lysine and arginine residues and found in the nucleus. The amino groups on lysine and arginine residues are protonated at the physiological pH (∼7.4) and acquire positive charges. Histones are divided into two classes: core histones, which include H2A, H2B, H3, and H4 and linker histones, which include the homologous H1 and H5. The C-terminal histone-fold domain (HFD) is the central globular domain of histones and it is involved in the formation of histone octamers. The unstructured N-terminal tail is commonly subjected to various post-translational modifications (PTMs) to perform other functions. Histone octamers are made by joining a middle (H3-H4)₂ tetramer unit with two (H2A-H2B) dimer units on both sides. The octamer functions as a bio spool for DNA, thus the negatively charged DNA molecule is attracted to the positively charged histone residues and wraps tightly around the octamer. Nearly, 147 DNA base pairs are wrapped about 2 times around each octamer forming a unit called nucleosome. Nucleosomes are linked by histone linkers (either H1 or H5) to form a stabilized higher-order structure known as chromatin that resembles beads on a string and serves as a compact assembly that condenses the nearly 2-m-long DNA strand into a chromatin which allows the DNA to fit within the tiny cell nucleus. This assembly also prevents the DNA molecule from becoming tangled or damaged. In addition to this crucial function, histones play critical roles in other functions through post-translational modifications (PTMs). The most common histone PTMs are methylation, acetylation and phosphorylation, which occur primarily on the lysine residues located on the N-terminal tails and can influence all DNA-associated functions, including gene transcription, chromatin assembly, DNA repair and replication.

A very important epigenetic mechanism that controls and mediates many fundamental biological processes is the site-specific methylation of lysine residues on histones. Unlike acetylation or phosphorylation, which convert the amino groups on lysine residues into uncharged amides, the methylation keeps these amino groups basic and positively charged under physiological conditions. The site-specific methylation of lysine residue 27 on the tail of H3 histone (abbreviated as H3K27) at the genomic region of target genes represses gene transcription and is mediated by the histone methyltransferase known as Polycomb Repressive Complex 2 (PRC2). The catalytic function of PRC2 requires at least three core activating subunits including suppressor of zeste 12 (SUZ12), embryonic ectoderm development (EED) and either the enhancer of zeste homologue 1 or the enhancer of zeste homologue 2 (EZH1 or EZH2). Both EZH1 and EZH2 are homologous proteins that can integrate into PRC2 in a mutually exclusive manner, showing different tissue and temporal distributions. In PRC2, EZH2 can directly bind the cofactor S-adenosyl methionine (SAM) to methylate the H3K27 site of histone once, twice or three times to form mono-, di-, or trimethylated species (named H3K27me1, H3K27me2 and H3K27me3 respectively), which act as repressive marks for gene transcription. PRC2-EZH1 displays lower activity than PRC2-EZH2, and can only catalyze the formation of the monomethyl (H3K27me1) and some dimethyl (H3K27me2) species. EED may bind H3K27me2/3 to allosterically enhance enzyme activity of PRC2 and promote spreading of the repressive marks.

EZH2 plays a critical function in both development stage and adult tissue homeostasis, and it has been closely associated with many diseases. Cancer studies have confirmed the overexpression of EZH2, SUZ12 and EED in many cancers, including but not limited to breast cancer, prostate cancer and hepatocellular carcinoma. Increased levels of H3K27me3 act as suppressive marks that halt gene transcription. Furthermore, EZH2 activating mutations, which lead to increased levels of H3K27me3, have been identified in diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), melanoma, and parathyroid adenocarcinoma patients.

Recent studies have implicated EZH2 in drug resistance in several breast cancer subtypes. Dysregulation of EZH2 activity promotes oncogenic transcription and contributes to immune evasion. For example, EZH2 represses the estrogen receptor gene 1 (Esr1) in HER2+ breast cancer; whereas its inhibition has resulted in restoring estrogen receptor (ER) expression and sensitizing tumor cancer cells to endocrine therapies like Tamoxifen. In addition, EZH2 acts downstream of PI3K-mTOR signaling and contributes to cancer stem-like and immunotherapy-resistant phenotypes in triple-negative breast cancer (TNBC). Thus, the inhibition of EZH2 is a promising therapeutic target to enhance immune visibility, restore tumor-suppressive pathways, and reverse drug-resistant states.

Studies have shown that inhibition of the methyltransferase activity of PRC2 by compounds that compete with the cofactor SAM or with compounds that bind directly to EED reverses high H3K27me3 state, reactivates expression of target genes and inhibits tumor growth/proliferation in DLBCL. It also frees the repressed T helper 1 (Th1) chemokines in tumor cells, and that results in enhanced T cell infiltration in ovarian and colorectal cancers. EZH2 has become a promising pharmacological target for treating DLBCL and other cancers. EZH2 also plays important roles in autoimmune diseases and related disorders. Therefore, there is a high need for identifying small molecules that can selectively inhibit EZH2 activity. The compounds of formula 1 in this patent application are potent inhibitors of EZH2 and may contribute to satisfying this need and provide treatment for diseases mediated by EZH2, or the PRC2-EZH2 complex such as cancer, autoimmune diseases and possibly other related disorders.

Key Structures

The inventors described structures and synthesis procedures for 77 compounds of formula 1. The following are selected representative examples of these compounds.

Biological Assay

• (a)EZH2 LC-MS Assay
• (b)ELISA (H3K27 Methylation) Assay

Biological Data

The compounds of formula 1 were tested using the EZH2 LC (a) and/or EZH2 ELISA (b) assays to measure their EZH2 inhibitory activity. The data obtained from testing the above representative examples using the two assays are listed in the following table as IC₅₀ in μM values.

Claims

Twenty claims. Claim 1: A method for treating a disease or condition mediated by EZH2, PRC2, or EZH2-PRC2 by a compound of formula 1. Claims 2–17: expanded definitions of formula 1 compounds. Claims 18–19: claim diseases that may be treated by compounds of formula 1 such as leukemia, multiple myeloma, gastric cancer, malignant rhabdoid tumor, hepatocellular carcinoma and many other forms of cancer. Claim 20: claims methods of drug administration (oral, parenteral, or rectal route).

Recent Review Articles

See References − .

The author declares no competing financial interest.