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Published on: December 21, 2019
Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening,
Siyuan Liu1, Jian Yu1, Xinrao Du1
1First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China.
Abstract:
The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1H-pyrrolo[2,3-b]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound 7w, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC50 values of 160.3 nM and 228 μM, respectively. Compound 7w showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.
Insights
Researchers identified novel 1H-pyrrolo[2,3-b]pyridine derivatives as transforming growth factor β (TGF-β) type 1 receptor (TGFβR1) inhibitors. Compound 7w effectively inhibited cancer cell viability and showed synergistic effects with sorafenib for potential anticancer therapies.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- The transforming growth factor β (TGF-β) type 1 receptor (ALK5) is crucial in the tumor microenvironment.
- Targeting TGFβR1 with small molecules is a promising strategy for cancer treatment.
Purpose of the Study:
- To discover novel TGFβR1 inhibitors based on the 1H-pyrrolo[2,3-b]pyridine scaffold.
- To evaluate the anticancer potential of identified compounds, particularly compound 7w.
Main Methods:
- Synthesis and screening of 1H-pyrrolo[2,3-b]pyridine derivatives.
- Inhibition assays for SMAD2/3 phosphorylation.
- Cell viability assays using Hep3B cells.
- Combination studies with sorafenib.
Main Results:
- A series of novel 1H-pyrrolo[2,3-b]pyridine derivatives targeting TGFβR1 were identified.
- Compound 7w demonstrated potent inhibition of SMAD2/3 phosphorylation (IC50 = 160.3 nM) and Hep3B cell viability (IC50 = 228 μM).
- Compound 7w exhibited synergistic anti-proliferation and pro-apoptotic effects when combined with sorafenib.
Conclusions:
- Compound 7w is a potent TGFβR1 inhibitor with significant anticancer activity.
- The identified compounds represent promising leads for developing novel anticancer therapeutics targeting the TGF-β pathway.
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