Vismodegib (GDC-0449)

Orally

MDCKII cells

GDC-0449 has entered into a phase II clinical trials in the treatment of basal cell carcinoma.

GDC-0449 (Vismodegib, HhAntag691) is a potent, novel and specific hedgehog inhibitor with IC50 of 3 nM and also inhibits P-gp with IC50 of 3.0 uM.

In 0.5% methyl-cellulose, 0.2% tween-80

GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. GDC-0449 prevents multiple ATP-binding cassette (ABC) transporters. GDC-0449 also blocks ABCG2, Pgp, and MRP1-important ABC transporters associated with MDR. GDC-0449 is a potent inhibitor of ABC transporters, ABCG2/BCRP and ABCB1/Pgp, and is a mild inhibitor of ABCC1/MRP1. In ABCG2-overexpressing HEK293 cells, GDC-0449 increases retention of the fluorescent ABCG2 substrate BODIPY-prazosin and resensitizes these cells to mitoxantrone. In Madin-Darby canine kidney II cells engineered to overexpress Pgp or MRP1, GDC-0449 increases the retention of calcein-AM and resensitizes them to colchicine. GDC-0449 also resensitizes human non-small cell lung carcinoma cells NCI-H460/par and NCI-H460/MX20, which overexpress ABCG2 in response to mitoxantrone, to mitoxantrone, and to topotecan or SN-38. The IC50 values of GDC-0449 for prevention of ABCG2 and Pgp are about 1.4 uM and 3.0 uM, respectively. [2] GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells. [3]

2 hours

421, 3

Data from [J Neurooncol , 2011, 105(3), 475-483], Vismodegib (GDC-0449)purchased from Selleck, Mouse medulloblastoma primary cells (U51669) showed inhibition of Gli1 by GDC-0499 in dose dependent manner. *P0.01.

2 years -20CPowder, 2 weeks4Cin DMSO, 2 months-80Cin DMSO