Tirbanibulin

SRC

431, 53

KX2-391 is in Phase 1 clinical trial for evaluation of it in elderly subjects with acute myeloid leukemia (AML).

9 nM (GI50), 9 nM (GI50), 9 nM (GI50), 9 nM (GI50), 9 nM (GI50), 9 nM (GI50)

In pre-clinical animal models of cancer, orally administered KX2-391 is shown to inhibit primary tumor growth and to suppress metastasis. [2]

Liver cell lines including Huh7, PLC/PRF/5, Hep3B, and HepG2 (NutriCyte, Buffalo, NY) are routinely cultured and maintained in basal medium containing 2% fetal bovine serum (FBS) at 37 C and 5% CO2. Cells are seeded at 4.0, 103/190 L and 8.0, 103/190 L per well of 96-well plate in basal medium containing 1.5% FBS. These are cultured overnight at 37 C and 5% CO2 prior to the addition of KX2-391, at concentrations ranging from 6, 564 to 0.012 nM in triplicates. Treated cells are incubated for 3 days. Ten microliters of 3-(4, 5-dimethylthiazol- 2-yl)-2, 5-diphenyltetrazolium bromide (MTT) solution (5 mg/mL) is then added to each well on day 3 and cells incubated for 4 hours. The formazan product is dissolved with 10% SDS in dilute HCl. Optical density at 570 nm is measured by using BioTek Synergy HT multiplatform microplate reader. For comparison of activity and potency, parallel experiments are performed using KX2-391. Growth inhibition curves, 50% inhibition concentration (GI50), and 80% inhibition concentration (GI80) are determined using GraphPad Prism 5 statistical software. Data are normalized to represent percentage of maximum response as well as reported in optical density at wavelength of 570 nm (OD570) signal format.

Tirbanibulin, the first clinical Src inhibitor (peptidomimetic class) that targets the peptide substrate site of Src, with GI50 of 9-60 nM in cancer cell lines. Phase 2.