A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors

AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA

“…AT101 has been administered to patients orally with a plasma half-life of 2 h [ 22 , 24 , 35 ]. We therefore approximated this exposure by following the expression of NOXA after removal of AT101 at 6 h. Surprisingly, there was a dramatic increase in NOXA protein peaking at 12–24 h ( Figure 5 B).…”

“…AT101 [(-)-gossypol] is the active isomer of gossypol, a polyphenolic dialdehyde derived from natural cottonseed originally intended as an anti-fertility agent and administered to more than 10,000 male subjects [ 21 ]. AT101 was subsequently described as a BH3 mimetic having high affinity for multiple anti-apoptotic proteins and was used as such in phase I/II clinical trials [ 22 , 23 , 24 ]. However, evidence showing AT101 as a bona fide BH3 mimetic was based on in vitro experiments that did not fully explore its effects in cells; hence these clinical trials failed to show any efficacy with AT101.…”

Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?

“…Although AT-101 showed potent response in a few trials, 33 the high level of cytotoxicity and low or moderate efficacy in many trials limits its further application in the clinic. 34 While few studies have shown that gossypol was orally applicable and well tolerated when applied in combination with other therapies, [34][35][36][37] most studies of gossypol as a single-agent reported considerable side effect, including hematologic toxicities and gastrointestinal motility. [38][39][40][41][42][43] Of note, some of the results in clinical trials showed that Bcl-2 protein levels were not significantly changed in peripheral blood mononuclear cells (PBMCs) of AT-101 treated patients, indicating AT-101 may not always be "on-target" in vivo.…”

Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review

“…However, phase II trial data of AT-101 posted in 2010 indicated that it did not generate the expected response (NCT00286780), so the company stopped the clinical development of this drug until the founders decided to continue research in China. Recently, clinical trials using AT-101 in combination with other drugs for the treatment of solid tumors have been reported, such as its combination with docetaxel to treat head and neck cancer [27], in combination with docetaxel and prednisone to treat castration-resistant prostate cancer [42], in combination with topotecan to treat small-cell lung cancer [26], in combination with paclitaxel and carboplatin for different carcinoma types [43], and in combination with cisplatin and etoposide for extensive-stage small-cell lung cancer [28]. Given the reported findings, it is reasonable to believe that AT-101 could be a potent inhibitor of Bcl-2.…”