PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Inhibitors of BRD4 as Potential Cancer Therapy Ahmed F. Abdel-Magid* Therachem Research Medilab (India) Pvt. Ltd., Jaipur, India
Patent Application Title:
Substituted [1,2,4]Triazolo[4,3-a]pyrazines as BRD4 Inhibitors
Patent Application Number: US 2016/0129001 A1
Publication date:
May 12, 2016
Priority date:
November 16, 2012
Priority Application:
EP 12192987.1
Inventors:
Engelhardt, H.; Gianni, D.; Smethurst, C.
Applicant:
Boehringer Ingelheim International GmbH, Ingelheim am Rhein (DE)
Disease Area:
Cancer
Summary:
The invention in this patent application relates to [1,2,4]triazolo[4,3-A]pyrazine derivatives represented generally by formula (I).
Bromodomain-containing protein 4 (BRD4)
Biological Target:
These compounds are BRD4 inhibitors and may provide useful treatments for diseases characterized by excessive or abnormal cell proliferation. Acetylation of histone in the nucleosomes is a modification that is associated with the activation of gene transcription. This modification changes the electrostatic interactions between the DNA and the histone octamer and can cause the weakening of these interactions. Furthermore, there are certain specific proteins that bind to acetylated lysine residues within histones to read the epigenetic code. Proteins that bind to acetylated lysine residues contain small (about 110 amino acid) distinct domains called bromodomains. These proteins can bind to acetylated lysine residues commonly but not exclusively in the context of histones. There are about 50 known proteins that contain bromodomains, and these proteins perform a range of specific functions within the cell. One of the families of bromodomain-containing proteins (BRDs) is the bromodomain and extra terminal domain (BET) family, which contains four members: BRD2, BRD3, BRD4, and BRD-T. The proteins in this family contain tandem bromodomains capable of binding two closely located acetylated lysine residues, thus increasing the specificity of the binding interactions. Recent studies have implicated BRD4 as a component of a recurrent t(15;19) chromosomal translocation. This chromosomal translocation expresses the tandem N-terminal bromodomains of BRD4 as an in-frame chimera with the nuclear protein in testis (NUT) protein. The resulting BRD4-NUT fusion oncoprotein causes a genetically defined aggressive form of human squamous carcinoma known as the NUT midline carcinoma (NMC), which is a very rare and aggressive cancer that affects young people. Functional studies in patientderived NMC cell lines have confirmed an essential role of BRD4-NUT oncoprotein in maintaining the proliferation and the differentiation block of these malignant cells. Other studies have identified an additional role for BRD4 as a critical sensitivity determinant in a genetically defined acute myeloid leukemia (AML) mouse model. The suppression of BRD4 activity led to robust antileukemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation. The studies of a broad array of mouse and human leukemia cell lines have also revealed that inhibition of BRD4 triggers MYC down-regulation. Therefore, BRD4 inhibitors may provide a means of suppressing the MYC pathway in a range of AML subtypes. The above findings indicate that BRD4 is an attractive therapeutic target for the treatment of cancer. BRD4 inhibitors such as the compounds described in this patent application may potentially provide a useful therapy for the prevention and/or treatment of diseases characterized by excessive or abnormal cell proliferation, such as cancer. Important Compound Classes:
Received:
r XXXX American Chemical Society
A
June 30, 2016
dx.doi.org/10.1021/acsmedchemlett.6b00259 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Key Structures:
Biological Assay:
PATENT HIGHLIGHT
The inventors described the synthesis of 61 compounds of formula (I) including the following representative examples:
BRD4-H4 Tetraacetylated Peptide Inhibition AlphaScreen The assay determines if the compounds inhibit the interaction between the first (BRD4-BD1) or the second (BRD4-BD2)
Biological Data:
bromodomain of BRD4 and the tetraacetylated histone H4 peptide The IC50 values obtained from testing the representative examples in the above assay are listed in the following table:
Recent Review Articles:
(1.) Valent, P.; Zuber, J. Cell Cycle 2014, 13 (5), 689 690. (2.) Garnier, J.-M.; Sharp, P. P.; Burns, C. J. Expert Opin. Ther. Pat. 2014, 24 (2), 185 199. (3.) French, Christopher A. Annu. Rev. Pathol.-Mech. 2012, 7, 247 265.
’ 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
dx.doi.org/10.1021/acsmedchemlett.6b00259 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
