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Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors
- Source :
- Eur J Med Chem
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- TGFβ is crucial for the homeostasis of epithelial and neural tissues, wound repair, and regulating immune responses. Its dysregulation is associated with a vast number of diseases, of which modifying the tumor microenvironment is one of vital clinical interest. Despite various attempts, there is still no FDA-approved therapy to inhibit the TGFβ pathway. Major mainstream approaches involve impairment of the TGFβ pathway via inhibition of the TGFβRI kinase. With the purpose to identify non-receptor kinase-based inhibitors to impair TGFβ signaling, an in-house chemical library was enriched, through a computational study, to eliminate TGFβRI kinase activity. Selected compounds were screened against a cell line engineered with a firefly luciferase gene under TGFβ-Smad-dependent transcriptional control. Results indicated moderate potency for a molecule with phthalazine core against TGFβ-Smad signaling. A series of phthalazine compounds were synthesized and evaluated for potency. The most promising compound (10p) exhibited an IC50 of 0.11 ± 0.02 μM and was confirmed to be non-cytotoxic up to 12 μM, with a selectivity index of approximately 112-fold. Simultaneously, 10p was confirmed to reduce the Smad phosphorylation using Western blot without exhibiting inhibition on the TGFβRI enzyme. This study identified a novel small-molecule scaffold that targets the TGFβ pathway via a non-receptor-kinase mechanism.
- Subjects :
- Cell Survival
Drug Evaluation, Preclinical
Smad Proteins
SMAD
01 natural sciences
Article
Chemical library
Small Molecule Libraries
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Transforming Growth Factor beta
Drug Discovery
Transcriptional regulation
Humans
Luciferase
Phosphorylation
Kinase activity
030304 developmental biology
Pharmacology
0303 health sciences
Tumor microenvironment
010405 organic chemistry
Chemistry
Kinase
Organic Chemistry
General Medicine
0104 chemical sciences
Cell biology
HEK293 Cells
Phthalazines
Receptors, Transforming Growth Factor beta
Signal Transduction
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 223
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....206dce3c2b4665b4c0a85d090764936e