Discovery and biological evaluation of phthalazines as novel non-kinase TGFβ pathway inhibitors

Anupreet Kharbanda, Lingtian Zhang, Debasmita Saha, Phuc Tran, Ke Xu, Ming O. Li, Yuet Kin Leung, Brendan Frett, Hong yu Li

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article number113660
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Nov 5 2021
Externally publishedYes


  • Cytokines
  • Non-kinase inhibitor
  • Pthalazine derivatives
  • TGF-β inhibitor
  • TGF-β pathway inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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