FRAX1036 is a selective inhibitor of p21-activated kinase 1 (PAK1), a serine/threonine kinase downstream of Rac1 and Cdc42 that is involved in tumorigenesis. It can induce apoptosis in breast cancer cells and has been shown to potentiate the activity of the microtubule stabilizing agent, docetaxel . Disruption of PAK1 via FRAX1036 has been used to inhibit oncogenic KRAS signaling in non-small cell lung cancer cells.
FRAX1036 is a PAK inhibitor with Kis of 23.3 nM, 72.4 nM, and 2.4 μM for PAK1, PAK2 and PAK4, respectively.
previous study demonstrated that the administration of docetaxel with either frax1036 or pak1 small interfering rna oligonucleotides was able to alter signaling to cytoskeletal-associated proteins dramatically, such as stathmin, and also able to induce microtubule disorganization and cellular apoptosis. in addition, the live-cell imaging data showed that the duration of mitotic arrest mediated by docetaxel could be significantly reduced by the treatment of frax1036, which was associated with increased kinetics of apoptosis [1].
in previous animal study, the untreated mice bearing kt21 transplants showed ventricular invasion, whereas ben-men grew at the injection site. efficacy results found that the treatment with frax1036 could lead to a slower tumor growth, with reduction in body mass index (bmi) signals of 37% when compared to vehicle cohort [2].
PAK1: 23.3 nM (Ki); PAK2: 72.4 nM (Ki); PAK4: 2.4 μM (Ki)
[1] ong cc et al. small molecule inhibition of group i p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. breast cancer res.2015 apr 23;17:59.
[2] chow hy et al. group i paks as therapeutic targets in nf2-deficient meningioma. oncotarget.2015 feb 10;6(4):1981-94.
