Benzamide, 3-[2-[2-(cyclopropylamino)-5-pyrimidinyl]ethynyl]-N-[3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-4-methyl-

Biological Activity

S116836, a potent, orally active BCR-ABL tyrosine kinase inhibitor (TKI), blocks both wild-type as well as T315I Bcr-Abl. S116836 potently inhibits the phosphorylation of BCR-ABL and induces apoptosis. S116836 inhibits growth of WT and T315I mutant BCR-ABL tumors and does not cause significant cardiotoxicity. S116836 also inhibits SRC, LYN, HCK, LCK and BLK, and receptor tyrosine kinases such as FLT3, TIE2, KIT, PDGFR-β. Antitumor activies[1][2][3]. S116836 (0.01-1 μM; 24 hours) significantly reduces the cellular proliferation of BaF3/WT and BaF3/T315I cells (IC50 values of 0.05 μM and 0.20 μM, respectively)[1].S116836 (0.01-1 μM； 24 hours) significantly downregulates the expression level of p-BCR-ABL in BaF3/WT cells[1].S116836 (0.01-1 μM; 24 hours) significantly downregulates the expression level of p-BCR-ABL in Imatinib-resistant BaF3/T315I cells[1].S116836 (0.01-1 μM; 24 hours) significantly downregulates the expression level of p-Crkl and p-STAT5 (downstream signaling proteins of BCR-ABL) in both BaF3/WT and BaF3/T315I cells[1].S116836 (0.1, 0.3, and 0.5 μM; 24 hours) arrests the BaF3/WT and BaF3/T315I cells in G0/G1 phase of the cell cycle[1].S116836 (0.3 and 0.5 μM; 24 hours) increases ROS production and decreases GSH levels in BaF3/WT and BaF3/T315I cells[1].S116836 (0.1, 0.3, and 0.5 μM; 24 hours) induces apoptosis in BaF3/WT and BaF3/T315I cells[1].SAHA and S116836 synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells[2].S116836 potently inhibits PDGFRα and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibits the growth of the WT and T674I FIP1L1-PDGFRα-expressing neoplastic cells. S116836 induces intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway[3]. S116836 (100 or 200 mg/kg; i.p.; q3d×6, athymic NCR nude mice) decreases the volume and weight of xenograft tumors expressing WT and T315I mutant BCR-ABL[1].S116836 (200mg/kg/d, oral gavage for 14 days) inhibits the growth of xenografted T674I-FIP1L1-PDGFRα cells in nude mice[3].

References

[1]. Gupta P, et al. Preclinical development of a novel BCR-ABL T315I inhibitor against chronic myeloid leukemia. Cancer Lett. 2020;472:132-141. [2]. Bu Q, et al. SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells. Cancer Biol Ther. 2014;15(7):951-962. [3]. Shen Y, et al. Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRα-expressing cells. Oncotarget. 2014;5(21):10407-10420.