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ACS Medicinal Chemistry Letters
 
ACS Med Chem Lett. 2016 March 10; 7(3): 205–206.
Published online 2016 February 1. doi:  10.1021/acsmedchemlett.6b00015
PMCID: PMC4789668

MALT1 Inhibitors May Potentially Treat Lymphomas and Autoimmune Disorders

Patent Application Title:Novel Pyrazolo Pyrimidine Derivatives and Their Use as MALT1 Inhibitors
Patent Application Number:WO 2015/181747 A1Publication date:3 December 2015
Priority Application:EP 14170408.0Priority date:28 May 2014
Inventors (and applicants for US only):Pissot Soldermann, C.; Quancard, J.; Schlapbach, A.; Simic, O.; Tintelnot-Blomley, M.; Zoller, T.
Applicant and Common Representative:for all designated States except US: Novartis AG; Lichtstrasse 35 CH-4056 Basel (CH)
Disease Area:Lymphomas, autoimmune disorders, or other MALT1-related disordersBiological Target:Mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1)
Summary:The invention in this patent application is related to pyrazolo pyrimidine derivatives represented generally by formula (I). These compounds are MALT1 inhibitors and may be useful for the treatment of several MALT1-related diseases or disorders. This may include, but is not limited to, autoimmune disorders and inflammatory diseases, asthma and chronic obstructive pulmonary disease (COPD), acute or chronic transplant rejection or graft versus host disease, cancers of hematopoietic origin or solid tumors including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and other B cell lymphomas.
Paracaspases are a family of caspase-like proteins that include the mucosa associated lymphoid tissue lymphoma translocation protein 1 (MALT1). Their prodomains contain a death domain and immunoglobulin domains. MALT1 acts as a scaffolding protein and possesses proteolytic activity mediated by its caspase-like domain. It plays an essential role in influencing immune responses. MALT1 combines with caspase recruitment domain-containing protein 11 (CARD11) and B-cell lymphoma/leukemia 10 (BCL10) to form a complex named CBM. The formation of CBM complex is critical for the activation of the transcription factor NF-κB. Aberrant activation of NF-κB is linked to many human lymphomas due to its ability to promote tumor survival. Studies have also shown that chromosomal translocations leading to formation of the constitutively active fusion protein API2-MALT1 [made from the fusion of cellular inhibitor of apoptosis 2 (API2) and MALT1] appear to cause an uncontrolled and stimulus-independent activation of NF-κB. Studies also suggest that the proteolytic function of MALT1 plays an important role in signaling cascades triggered by innate cell receptors like Dectin receptors and in signaling cascades triggered by G-protein coupled receptors in many cell types.
MALT1 has become an increasingly attractive therapeutic target to develop new treatment of certain lymphomas and autoimmune disorders. Inhibitors of the proteolytic activity of MALT1 are known in the art, and many have displayed activities in preclinical lymphoma models. However, there is still a need to develop new effective MALT1 inhibitors such as the compounds described in this patent application that may potentially lead to the development of new drugs to treat certain lymphomas, autoimmune disorders, and many other MALT1-related disorders.
Important Compound Classes:
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Key Structures:The inventors described the synthesis and structures of 127 examples of formula (I) including the following representative examples:
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Biological Assay:MALT1 biochemical assay
cIAP2-MALT1-driven NF-κB reporter gene assay (RGA) in HEK293
Human IL2 promoter reporter gene assay (RGA} in Jurkat cells
Biological Data:The inventors reported the biological data obtained from testing the compounds of the inventions using the above assays. The data obtained from the above representative examples are listed in the following table:
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Recent Review Articles:1. Hailfinger S.; Lenz G.; Thome M.Curr. Opin. Chem. Biol. 2014, 23, 47–55. [PubMed]
2. Fontan L.; Melnick A.Clin. Cancer Res. 2013, 19 (24), 6662–6668. [PubMed]
3. Rosebeck S.; Lucas P. C.; McAllister-Lucas L. M.Future Oncol. 2011, 7 (5), 613–617. [PubMed]

Notes

The authors declare no competing financial interest.


Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society