AT-101

Uses

(R)-(-)-Gossypol acetic acid (AT-101 (acetic acid)) is the levorotatory isomer of a natural product Gossypol. AT-101 is determined to bind to Bcl-2, Mcl-1 and Bcl-xL proteins with Kis of 260±30 nM, 170±10 nM, and 480±40 nM, respectively.

Biological Activity

AT-101, the R-(-) enantiomer of Gossypol acetic acid, binds to Bcl-2, Bcl-xL and Mcl-1 with K_i of 0.32 μM, 0.48 μM and 0.18 μM; no Inhibits the BIR3 domain and BID. Phase 2.

in vitro

AT-101 inhibits a diverse panel of lymphoproliferative malignancies with IC50 of 1.2 μM to 7.4 μM after 24 hours of treatment, 0.7 μM to 3.9 μM after 48 hours of treatment, IC50 of 72 hours after treatment 0.3 μM to 1.7 μM. AT-101 (10 μM) disrupts mitochondrial membrane potential (Δψm) in a concentration- and time-dependent manner in diffuse large B-cell and mantle cell lymphoma cell lines.

in vivo

AT-101 treated SCID beige mice bearing RL-DLBCL xenografts, it was still detectable in plasma, with a mean concentration of 0.49 μM in the 35 mg/kg group and 0.39 μM in the 200 mg/kg group . In SCID beige mice treated with it, peak plasma concentrations were observed after 30 minutes, and the mean plasma concentration in the 200 mg/kg group was almost 4-fold higher than that in the 35 mg/kg group (7.88 μM and 27.78 μM, respectively).

target

IC 50

Mcl-1: 170 nM (Ki); Bcl-2: 260 nM (Ki); Bcl-xL: 480 nM (Ki); Autophagy

References

[1] Oliver CL, et al. In vitro effects of the BH3 mimetic, (-)-Gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004 Nov 15;10(22):7757-63. DOI:10.1158/1078-0432.CCR-04-0551
[2] Sun Y, et al. Apogossypolone, a nonpeptidic small molecule inhibitor targeting Bcl-2 family proteins, effectively inhibits growth of diffuse large cell lymphoma cells in vitro and in vivo. Cancer Biol Ther. 2008 Sep;7(9):1418-26. DOI:10.4161/cbt.7.9.6430