NVP-TAE226

Herein, 24 diaminopyrimidine derivatives were designed and synthesized based on TAE-226...Compound A12 was also selected for molecular docking studies and the prediction of molecular properties and drug-like properties. These results indicated that compound A12 could be used as a potential lead compound targeting FAK for further development.

Finally, FERMT1 overexpression may be sensitive to chemotherapy drugs such as Palbociclib, AM-5992 and TAE-226. FERMT1 can serve as a diagnostic and prognostic marker of PAAD, which is connected with immune cell infiltration and the modulation of mA and necroptosis.

The most active compound 8f not only significantly inhibited FAK kinase activity (IC = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC = 0.126 μM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC.

MY-1259 exhibited more effective antitumor effect in vivo than the HDAC inhibitor SAHA and FAK inhibitor TAE-226 alone or in combination, showing the advantages of FAK/HDAC dual inhibitors in the treatment of gastric cancers. Therefore, the results in this work suggested that inhibition of FAK and HDAC by MY-1259 might represent a promising strategy for the treatment of gastric cancers.

Inhibiting FAK activity with TAE226 observably impairs the tumor-promoting effects. In conclusion, ROCK1 promotes LSCC tumorigenesis and progression via the FAK signaling pathway, targeting the ROCK1 molecule may represent potential targets for clinical LSCC treatment.

Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy.

TAE226 is a dual inhibitor of FAK and insulin-like growth factor-I receptor (IGF-IR), while PF-562,271 is a dual inhibitor of FAK and proline-rich tyrosine kinase 2. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.