Uses
A synthetic, orally bioavailable small molecule and non-ATP competitive Src tyrosine kinase inhibitor with an IC50 of average 72 nM.
Biological Activity
kx2-391 is a highly selective inhibitor of src kinase with ic50 value of 20nm [1].kx2-391 is a non-atp competitive inhibitor of src. it is the first inhibitor that targets src kinase within the substrate binding site. kx2-391 inhibits src catalyzed trans-phosphorylation of fak, shc, paxillin as well as src kinase autophosphorylation. kx2-391 has no effects on pdgfr, egfr, jak1, jak2 and lck demonstrating it as a selective inhibitor. it is also found to be an inhibitor of tubulin polymerization through binding to the unique confirmation on heterodimeric tubulin. in cellular assays, kx2-391 shows growth inhibition in nih3t3/c-src527f cells and syf/c-src527f cells with gi50 values of 23nm and 39nm, respectively [1, 2].since src acts as a regulator in cell proliferation survival, motility and invasiveness, kx2-391 is potent against a variety of solid tumors and many leukemia tumors. it is shown to inhibit primary tumor growth and to suppress metastasis [2].
Mechanism of action
Tirbanibulin inhibits Src kinase and interferes with the signal transduction pathway of tumor cells, thereby inhibiting tumor growth.
Synthesis
Chloro compound 111 is subjected to alkylation reaction with 4-bromophenol to generate ether 112. Pyridylboronic acid 114 is synthesized from the corresponding bromide 113 using Miyaura coupling, and then subjected to Suzuki coupling reaction with ether 112 to generate ether 115. Fluoropyridine is deprotonated and then subjected to substitution reaction with acetonitrile. The above-mentioned substitution product is then treated in benzoxazole using acid and benzylamine at high temperature. Through the above steps, tibaranibulin is obtained with an overall yield of 58%.
in vivo
Orally administered Tirbanibulin (KX2-391) is shown to inhibit primary tumor growth and to suppress metastasis, in pre-clinical animal models of cancer[2].
References
[1] fallah-tafti a, foroumadi a, tiwari r, et al. thiazolyl n-benzyl-substituted acetamide derivatives: synthesis, src kinase inhibitory and anticancer activities. european journal of medicinal chemistry, 2011, 46(10): 4853-4858.
[2] naing a, cohen r, dy g k, et al. a phase i trial of kx2-391, a novel non-atp competitive substrate-pocket-directed src inhibitor, in patients with advanced malignancies. investigational new drugs, 2013, 31(4): 967-973.
