Background:

IC50: 0.1-88 nM

PX 866 is a PI3K inhibitor.

Phosphoinositide (PtdIns)-3-kinases can phosphorylate membrane PtdIns and there are 8 mammalian PtdIns-3-kinases that are divided into three main classes based on its sequence homology and substrate preference.

In vitro: In previous study, PX 866 was identified to be able to inhibit purified PtdIns-3-kinase and PtdIns-3-kinase signaling that was measured by phospho-Ser473-Akt levels in HT-29 colon cancer cells [1].

In vivo: Animal study found that PX-866 treatment at 10 mg/kg to mice could inhibit phospho-Ser473-Akt in HT-29 colon tumor xenografts up to 80% with recovery taking over 48 hours after oral administration but more rapidly after iv or ip route. In addition, PX-866 had in-vivo antitumor activity against s.c. OvCar-3 human ovarian cancer and A-549 human lung cancer xenografts in immunodeficient mice. Moreove, PX-866 could also increase the antitumor activity of cisplatin against A-549 xenografts and radiation treatment against OvCar-3 xenografts [1].

Clinical trial: In a previous study, PX-866 was administered at 4–8 mg daily with docetaxel 75 mg/m2 every 21 days, and the results showed that the treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity [2].

参考文献:
[1] N.  T. Ihle, R. Williams, S. Chow, et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Molecular Cancer Therapeutics 3(7), 763-772 (2004).
[2] Bowles DW, Ma WW, Senzer N, Brahmer JR, Adjei AA, Davies M, Lazar AJ, Vo A, Peterson S, Walker L, Hausman D, Rudin CM, Jimeno A.  A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer. 2013 Sep 3;109(5):1085-92.