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Published on: June 23, 2019
Novel Functionalized Pyrrolopyridines to Target Brk
Erik Schmidt1, Jannis von Veh1, Anne-Christin Sarnow1
1Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
Background:
Increasing resistance against protein kinase inhibitors used in cancer therapies enforces the search for novel target structures to be addressed with favourable small-molecule inhibitors. One of these novel target structures is the tyrosine kinase Brk that is known to play a prominent role in breast cancer progression. Moreover, Brk overexpression in various kinds of cancer is associated with poor outcomes, making Brk an interesting target structure for potential treatment. So far, no class of promising Brk inhibitors has been identified.
Methods:
We synthesized novel functionalized pyrrolopyridines in one- and two-step reactions under substitution of the molecular scaffold and the 4-aniline residue, respectively. They were evaluated as inhibitors of Brk and HER2 in a radiolabelled enzyme assay.
Results:
The most favourable substituents for Brk inhibitory activity at the aniline residues were 3-hydroxy functions combined with either bromo or nitro substituents at the molecular scaffold. Those compounds, as well as bromo- and nitro-substituted compounds, also showed the best HER2 inhibitor activities.
Conclusions:
Novel pyrrolopyridines were discovered to be a promising class of nanomolar Brk inhibitor with additional HER2 activities to further strengthen Brk inhibitory activity in prospective anticancer therapies. Thus, the first class of Brk inhibitors could be identified.
Insights
Researchers identified novel pyrrolopyridines as potent inhibitors of Brk (Biliary system receptor kinase), a key target in breast cancer. These compounds also inhibit HER2, offering a promising new class of small-molecule inhibitors for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Cancer therapies face increasing resistance to protein kinase inhibitors.
- Brk tyrosine kinase is a novel target implicated in breast cancer progression and poor patient outcomes.
- No effective Brk inhibitors have been identified previously.
Purpose of the Study:
- To discover and develop novel small-molecule inhibitors targeting Brk.
- To explore pyrrolopyridine derivatives as potential Brk inhibitors.
- To evaluate the inhibitory activity against Brk and HER2 kinases.
Main Methods:
- Synthesis of novel functionalized pyrrolopyridines via one- and two-step reactions.
- Modification of the molecular scaffold and 4-aniline residue.
- Enzyme inhibition assays using radiolabeled Brk and HER2.
Main Results:
- Specific substituents on pyrrolopyridines enhanced Brk inhibitory activity.
- 3-hydroxy and bromo/nitro substituents on aniline residues were most effective for Brk inhibition.
- The synthesized compounds also demonstrated significant HER2 inhibitory activity.
Conclusions:
- Novel pyrrolopyridines represent a promising class of nanomolar Brk inhibitors.
- These compounds exhibit dual inhibitory activity against Brk and HER2.
- This discovery provides the first class of Brk inhibitors for potential anticancer therapies.
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