(R)-(-)-Gossypol acetic acid (AT-101 (acetic acid))

(R)-(-)-Gossypol (AT-101) acetic acid, the R-(-) enantiomer of Gossypol acetic acid, binds with Bcl-2, Bcl-xL and Mcl-1 with Ki of 0.32 μM, 0.48 μM and 0.18 μM in cell-free assays; does not inhibit BIR3 domain and BID. AT-101 simultaneously triggers apoptosis and a cytoprotective type of autophagy. Phase 2.

AT-101 inhibits a panel of different lymphoproliferative malignancies with IC50 ranged from 1.2 μM to 7.4 μM. AT-101 (10 μM) disrupts the Δψm in a concentration- and time-dependent manner in a diffuse large B-cell and in mantle cell lymphoma lines. AT-101 (1 μM or 2 μM) combined with carfilzomib (6 nM or 10 nM) induces apoptosis in HBL-2 and Granta cell lines. [2] AT-101 (20 μM for 24 hours) results in a median 72% apoptosis and down-regulation of Mcl-1 in CLL lymphocytes in both suspension culture as well as stromal coculture. Stromal cells express undetectable levels of antiapoptotic but high levels of activated ERK and AKT proteins and has low or no apoptosis with AT-101. [3] AT-101 induces apoptosis in a time- and dose-dependent fashion, with ED50 values of 1.9 mM and 2.4 mM in Jurkat T and U937 cells, respectively. AT-101 (10 μM) combined with radiation (32 Gy) induces more apoptosis than radiation alone and exceeds the sum of the effects caused by the single agent treatments. AT-101 activates SAPK/JNK in a dose- and time-dependent manner. [4] AT-101 (10 ?M) induces apoptosis through activation of caspase-9, -3, and -7 in VCaP Cells. AT-101 (10 ?M) decreases Bcl-2 and Mcl-1 expression in VCaP cells. [5] AT-101 (< 20 μM) is able to inhibit the growth of multiple myeloma cells despite the stimulatory growth effects provided by stromal cells in the bone marrow milieu. AT-101 (10 μM) induces apoptosis in multiple myeloma cells via the activation of caspases 3, caspases 9 and PARP. AT-101 (10 μM) promotes apoptosis in multiple myeloma cells by disrupting the Bax/Bcl-2 ratio and the mitochondrial membrane potential. [6]

AT-101 is still detectable in plasma with average concentrations of 0.49 μM for the 35 mg/kg group and 0.39 μM for the 200 mg/kg group in SCID beige mice bearing RL-DLBCL xenograft. AT-101 peak plasma concentration is observed after 30 minutes of administration of the drug in both the dose levels, with the 200 mg/kg group showing a plasma average concentration almost 4 times greater than the 35 mg/kg group (7.88 μM and 27.78 μM respectively) in SCID beige mice. AT-101 (25 mg/kg to 100 mg/kg, orally) indefinitely results in earlier onset of weight loss equivalent to more than 10% of the pretreatment weight and death in SCID beige mice. AT-101 (35 mg/kg, orally per day for 10 days) plus intraperitoneal cyclophosphamide (Cy) and intraperitoneal rituximab (R) show significantitumor volume control compared to any other treatment group. [2] AT-101 (15 mg/kg, p.o., 5 days/week) as a single agent in intact mice significantly reduces the development of VCaP tumor growth compared to untreated tumors at weeks 2 to 6. AT-101 in combination with surgical castration delays the onset of androgen-independent VCaP tumor growth compared to castration-only or AT-101-only groups in mice. [5]

[1] Wang G, et al. J Med Chem. 2006, 49(21), 6139-6142. [2] Paoluzzi L, et al. Blood, 2008, 111(11), 5350-5358. [3] Balakrishnan K, et al. Blood, 2009, 113(1), 149-153.