This discovery never has shown that gossypol, the active enantiomer of gos sypol, binds to anti apoptotic members of the Bcl 2 fam ily, Bcl 2, Bcl XL and Mcl 1, with nanomolar affinities and this active enantiomer has been tested in clinical trails for treatment of patients with advanced malignancies. In clinical trials, gossypol has been associated with side effects, such as emesis and diarrhea, because of the two reactive aldehyde groups. ApoG2 has been designed and synthesized with the reactive groups completely removed in order to minimize side effects. In addition, ApoG2 has superior stability under both stress and nor mal conditions compared to gossypol. It is notable that our study is the first on ApoG2 in FL. The goals of new agents such as ApoG2, are to have higher binding affinity to its targets.

ApoG2 has greater than 8 fold binding affinity to Bcl 2 over its predecessors TW 37 and gossypol. In this study, we have shown a potent anti lymphoma effect on FL. ApoG2 shows an IC50 of 9 and 18 fold lower when compared to TW 37 or gos sypol. When compared to HA14 1, which is a SMI to Bcl 2 used against leukemia cell lines HL60 and Inhibitors,Modulators,Libraries K562, ApoG2 has a IC50 which is 200 fold lower. The SMI ABT 737 has a considerably lower IC50 when used against FL cell lines, but ABT 737 does not bind to Mcl 1 and thus Mcl 1 expression could result in resistance. In comparison, ApoG2 targets all these three anti apop totic proteins. In our study, ApoG2 is effective against FL, pre B acute lymphoblastic leukemia, mantle Inhibitors,Modulators,Libraries cell lymphoma, marginal zone lymphoma, as well as chronic lymphocytic leukemia.

Therefore, ApoG2 could potentially be a more effective drug in the lymphoma clinic Inhibitors,Modulators,Libraries spanning a greater array of patients. With the binding of ApoG2 to Bcl 2 family of proteins, it would be expected that ApoG2 would lead to activation of downstream apoptotic proteins. The mechanism of action of ApoG2 has not been elucidated in FL. We show here Inhibitors,Modulators,Libraries that ApoG2 can activate the initiator caspase 9, and the effector caspase 3, and induce caspase cleavage in nanomolar concentrations. Moreover, ApoG2 can lead to the activation of caspase 8 which serves as amplification loop together with caspase 3. PARP and AIF have been implicated in the final stages of apoptosis. They play a role in the chromatin condensation and DNA fragmen tation. We show that ApoG2 activates PARP and AIF in the nanomolar range.

These findings clearly demonstrate that ApoG2 can acti vate the Bcl 2 apoptotic pathway in vitro. The exact mech anism of action of ApoG2 is unclear. Likely mechanisms Inhibitors,Modulators,Libraries are that ApoG2 binds to Bcl 2 and prevents its association Cabozantinib supplier with BH3 only pro apop totic proteins, thus unleashing the pro apoptotic proteins to participate in the apoptotic response. Work in our lab oratory is being done to further elucidate the mechanism of ApoG2 action.