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Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against
Peng Peng1, Xiaoyan Qiang1, Guoyu Li1
1Department of Medicinal Chemistry, Pharmacology, Project Management, Drug Metabolism and Pharmacokinetics, TransThera Sciences (Nanjing), Inc., Nanjing, Jiangsu, P.R. China.
Abstract:
Triple-negative breast cancer (TNBC) is a highly heterogeneous cancer lacking actionable targets. Using a phenotypic screen of TNBC cells, we discovered a novel multiple kinase inhibitor tinengotinib (TT-00420) that strongly inhibited Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R in biochemical assays. Exposure to tinengotinib specifically inhibited proliferation across all subtypes of TNBC in vitro and in vivo, while leaving luminal breast cancer cells intact. Incubation of HCC1806 with tinengotinib led to dose-dependent downregulation of genes essential for TNBC cell growth and proliferation. Studies revealed that the potential mechanism of action of tinengotinib involved, predominantly, inhibition of Aurora A or B kinase activity, while inhibition of other pathways contributed to suppression of potency and activity. In vitro treatment of TNBC cell lines or in vivo administration in a syngeneic model with tinengotinib resulted in up-regulation of CXCL10 and 11 or diminished tumor-associated macrophage (TAM) infiltration. Tinengotinib represents a novel combinatorial inhibitory mechanism to treat TNBC. The phase I trial of tinengotinib was completed (ClinicalTrials.gov identifier: NCT03654547).
Insights
Tinengotinib, a novel kinase inhibitor, effectively targets triple-negative breast cancer (TNBC) by inhibiting key growth pathways. This new treatment shows promise for TNBC patients, with a completed Phase I clinical trial.
Area of Science:
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) is a heterogeneous cancer subtype with limited targeted treatment options.
- The lack of actionable targets in TNBC necessitates the development of novel therapeutic strategies.
Purpose of the Study:
- To identify and characterize a novel small molecule inhibitor for TNBC.
- To investigate the efficacy and mechanism of action of tinengotinib in TNBC models.
Main Methods:
- Phenotypic screening of TNBC cells to identify potential inhibitors.
- Biochemical assays to determine kinase inhibition profiles of tinengotinib.
- In vitro and in vivo studies using TNBC cell lines and syngeneic models.
Main Results:
- Tinengotinib demonstrated potent inhibition of multiple kinases including Aurora A/B, FGFRs, VEGFRs, JAK1/2, and CSF1R.
- Tinengotinib selectively inhibited proliferation of TNBC cells in vitro and in vivo, sparing luminal breast cancer cells.
- Mechanism of action involves Aurora A/B kinase inhibition, leading to gene downregulation and immune modulation (CXCL10/11 upregulation, reduced TAM infiltration).
Conclusions:
- Tinengotinib exhibits a novel combinatorial inhibitory mechanism effective against TNBC.
- Tinengotinib represents a promising therapeutic candidate for triple-negative breast cancer treatment.
- A Phase I clinical trial for tinengotinib in TNBC patients has been successfully completed.
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