Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors Journal Article
| Authors: | Kharbanda, A.; Zhang, L.; Saha, D.; Tran, P.; Xu, K.; Li, M. O.; Leung, Y. K.; Frett, B.; Li, H. Y. |
| Article Title: | Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors |
| 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. © 2021 |
| Keywords: | cytokines; non-kinase inhibitor; pthalazine derivatives; tgf-β inhibitor; tgf-β pathway inhibitor |
| Journal Title: | European Journal of Medicinal Chemistry |
| Volume: | 223 |
| ISSN: | 0223-5234 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2021-11-05 |
| Start Page: | 113660 |
| Language: | English |
| DOI: | 10.1016/j.ejmech.2021.113660 |
| PROVIDER: | scopus |
| PUBMED: | 34246853 |
| PMCID: | PMC9472513 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 August 2021 -- Source: Scopus |
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