The enantiomer is associated with increased activity in many bioassays and these two patents deliver a procedure for preparation of gossypol enantiomer and its acetic acid co crystal with large purity for clinical utilization. The orally attainable gossypol enantiomer AT 101 has become tested for its security and efficacy in numerous clinical trials . A phase I II examine was performed combining AT 101 with topotecan in patients with relapsed and refractory minor cell lung cancer . The observed response costs did not meet the criteria for extra enrollment, but sufferers with secure illness showed the very best response plus the median time to progression was favorable . Within a multi institution phase I II trial, evaluation of AT 101 like a single agent in men with prostate cancer showed some evidence of decline of prostate distinct antigen and a clinical trial combining AT 101 with androgen deprivation is in progress .
The maximum tolerated dosage of AT 101 is 40 mg day and it truly is at this time becoming assessed in phase II clinical trials in blend with lenalidomide for CLL, and in combination with JAK2 inhibitor docetaxel is remaining tested in sufferers with recurrent, locally sophisticated or metastatic squamous cell carcinoma of the head and neck. AT 101 can also be undergoing phase II clinical trials as being a single agent in patients with recurrent, metastatic, or major unresectable adrenocortical carcinoma. A 2006 patent application from University of Michigan claims 4 new gossypol analogs, gossypolic acid, gossypolonic acid, apogossypol and apogossypolone , and in vitro activity making use of panel of breast cancer cell lines and in vivo efficacy of apogossypolone inside a prostate Computer three xenograft model.
Whilst, gossypolic acid and gossypolonic acid had been located to be much more potent than gossypol with K Camptothecin i values of 120 and 280 nM respectively towards Bcl two, while in the cell growth inhibition assays using prostate cancer Pc 3 cells IC50 values were ten uM for the two of the compounds. 1 conceivable explanation for this is often that the two acid groups are negatively charged at physiological condition and are so prevented from getting into cells. Without a doubt, apogossypol and apogossypolone, analogs lacking the carboxylic group, are two 9 fold additional potent than gossypol in cell growth inhibition assay by using breast cancer cell lines. The binding affinity of apogossypolone was determined to be Ki 76 nM, 51 nM and one,270 nM against Bcl 2, Mcl 1 and Bcl xL respectively. In addition, as was predicted that elimination within the aldehydes will considerably lower the toxicity, apogossypolone showed eight fold greater highest tolerated dose than gossypol in oral and intravenous routes of administrations.
Presently apogossypolone is from the preclinical phase of testing.