Targeted Tubulin Inhibitor
Tesetaxel stabilizes cytoskeletal structures known as microtubules. This effect induces potent cytotoxicity in a wide range of tumor cell types. Microtubule stabilization occurs when tesetaxel binds the beta-tubulin subunit in assembled microtubules, thus “locking” them in place. The chemical structure of tesetaxel appears below.
Preclinical studies have shown that tesetaxel inhibited tubulin depolymerization, which resulted in the inhibition of mitosis by arresting tumor cells at G2/M phase. The cytotoxic activity of tesetaxel against various types of human tumor cell lines was about 10-fold and 3-fold greater than paclitaxel and docetaxel, respectively. In particular, tesetaxel exhibited much greater cytotoxicity against multidrug-resistant cell lines that constitutively over-expressed pgp. As shown in the table below, the anti-tumor activity of tesetaxel against pgp-expressing cells was greater than paclitaxel and docetaxel both in vitro and in vivo.
Cell lines
|
IC50 (ng/ml)
|
Tesetaxel
|
Paclitaxel
|
Docetaxel
|
All Tumor Cell Lines (n=23)
|
0.544
|
5.58
|
1.73
|
P-gp negative cell lines (n=17)
|
0.455
|
1.79
|
0.774
|
P-gp positive cell lines (n=6)
|
0.780
|
15.7
|
4.
|
Reference: Data on file, Genta Incorporated
