BX-320

BX-320 is a selective, ATP-competitive, orally acitive, and direct PDK1 inhibitor with an IC50 of 30 nM in a direct kinase assay format. BX-320 also induces apoptosis. Anticancer effect[1].

Signaling Pathways >> PI3K/Akt/mTOR >> PDK-1

Research Areas >> Cancer

BX-320 binds to the ATP binding site of PDK1. BX-320 also inhibits Chck1, c-Kit, KDR, PKA, CDK2b/cyclin E, GSK3β, PKC with IC50s of 0.82, 0.89, 1.4, 1.4, 1.5, 4.0, and 5.7 μM, respectively[1]. BX-320 blocks PDK1/Akt signaling in tumor cells and inhibits the anchorage-dependent growth of a variety of tumor cell lines in culture or induces apoptosis[1]. BX-320 inhibits the growth of MDA-468 breast cancer cells (IC50=0.6 μM) and induces apoptosis. BX-320 promotes a 12-fold induction of caspase-3/7 activity after 48 h of treatment (IC50=0.5 μm), indicating a strong proapoptotic response[1]. BX-320 (0.3-10 μM; for 18 hours) greatly reduces the amount of both p-Thr308-Akt and p-Thr386-S6K1[1]. Cell Proliferation Assay[1] Cell Line: MDA-468 breast cancer cells Concentration: 31.6 nM, 100 nM, 316.22 nM, 1 μM, 3.162 μM, 10 μM, and 31.6 μM Incubation Time: 72 hours Result: Blocked the growth of MDA-468 cells (IC50=0.6 μM), which are PTEN-negative breast tumor cells expressing high levels of activated Akt. Western Blot Analysis[1] Cell Line: PC-3 cells Concentration: 0, 0.3, 1, 3, 10 μM Incubation Time: 18 hours Result: Reduced the amount of both phospho-Thr308-Akt and phospho-Thr386-S6K1.

BX-320 (oral dosing with 200 mg/kg, twice a day for 21 days) shows efficacy in a blood-borne metastasis model. BX-320 inhibits the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. BX-320 has efficacy in an in vivo tumor model, which may reflect an inhibition of productive implantation of tumor cells in the lung or an inhibition of subsequent tumor growth[1]. Animal Model: Athymic (nu/nu) female mice, 6-8 weeks old[1] Dosage: 200 mg/kg; dose volume was 10 mL/kg Administration: Oral gavage twice daily (12 h apart) Result: Significantly inhibited the growth of lung tumors in this model.

[1]. Richard I Feldman, et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem. 2005 May 20;280(20):19867-74.