Important Compound Classes
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Title
Proteolysis Targeting Chimera (PROTACS) as Degraders of SMARCA2 and/or SMARCA4
Patent Publication Number
WO 2020/078933 A1
Publication Date
April 23, 2020
Priority Application
EP 18200596.7
Priority Date
October 16, 2018
Inventors
Ciulli, A.; Dank, C.; Diers, E.; Farnaby, W.; Roy, M.; Steurer, S.; Trainor, N.
Assignee Company
Boehringer Ingelheim International GMBH; Binger Strasse 173, 55216 Ingelheim AM Rhein (DE).
Disease Area
Cancer
Biological Target
SMARCA2 and SMARCA4
Summary
The SMARCA subgroup of genes belong to the SWI1/SNF1 family that provide instructions for making chromatin remodeling and repair. Chromatin is highly condensed DNA and protein that forms chromosomes within the nucleus of eukaryotic cells, and the structure can be remodeled to alter how tightly DNA is packaged. SWI/SNF complexes regulate genes involved in many processes, which includes repair of damaged DNA, replication of DNA, control of cell growth, division, and maturation. SMARCA4 (BRG1) and SMARCA2 (BRM) are two crucial components of the SWI/SNF complex that share about 75% identity at the protein level. While SMARCA4 is the most frequently mutated chromatin remodeling ATPase in cancer, the SMARCA2 protein and other SWI/SNF subunits are thought to act as tumor suppressors.
In solid tumors, SMARCA4 acts as a tumor suppressor; however, in acute myeloid leukemia it is required to maintain the oncogenic transcription program and also facilitate proliferation. The selective suppression of SMARCA2 activity has been proposed as a therapeutic concept for SMARCA4 mutated cancers. Small molecule ligands targeting the bromodomains of SMARCA2/4 have been reported. However, cells lacking SMARCA4 activity are vulnerable to the loss of SMARCA2, and SMARCA2/4 inhibitors have failed to demonstrate the antiproliferative effects. There are reports that show that re-expression of SMARCA2 variants in cells, where the endogenous protein had been suppressed, indicates that an intact bromodomain is not required to maintain proliferation. Thus, the SMARCA2/4 inhibitors are precluded from use for the treatment of SMARCA4 mutant cancers.
In contrast to classical small molecule inhibitors, PROTAC driven degradation functions in a substoichiometric nature and thus requires lower systemic exposures to achieve efficacy. PROTACs have been shown to display higher degrees of selectivity for protein degradation than the target ligand itself as a result of complementarity differences in the protein–protein-interaction interfaces of the formed ternary complexes. Furthermore, PROTACs promise to expand the druggable proteome as degradation is not limited to the protein domain functionally responsible for the disease. Therefore, PROTAC targeting the nonfunctional bromodomain of SMARCA2/4 should offer a therapeutic strategy to exploit the vulnerability of the SMARCA2 in SMARCA4 mutated cancer cells.
The present Patent Highlight shows representative PROTAC compounds that directed the degrading of SMARCA2 and/or SMARCA4 and are used for the treatment or prevention of cancer or disease condition associated with the modulation of SMARCA2/4.
Key Structures
Biological Assay
Surface plasmon resonance (SPR) experiments were performed on Biacore 8K or T200 instruments. For the protein degradation assay, nonsmall lung cancer (NSCLC) cell lines (A549) were used such that the cells expressed both SMARCA2 and SMARCA4. Proliferation assays that determined ATP content were measured using CellTiterGlo.
Biological Data
The table below
shows the degradation
activity of SMARCA2 and SMARCA4 in A549 cells.
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The author declares no competing financial interest.