Reas recent studies suggest improved survival with tFL in the rituximab era [166, 183], raising the possibility that rituximab might partially counter the adverse impact of genomic changes leading to transformation. Thus, it will be important in the future to assess whether BCL2 KF-89617 site mutation status correlates with outcome in FL treated with rituximabcontaining chemoimmunotherapy.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptBiochim Biophys Acta. Author manuscript; available in PMC 2016 July 01.Correia et al.Page4. Targeting Bcl-2 as an anticancer strategy4.1 Small molecule inhibitors of Bcl-2 family proteins Because Bcl-2 overexpression contributes to the pathogenesis of various lymphoid neoplasms, particularly FL and CLL [17, 93, 94, 121], and possibly solid tumors [80], there has been substantial effort to develop Bcl-2 inhibitors as therapeutic agents. A combination of nuclear magnetic resonance-based binding assays and fluorescence polarization displacement assays [184, 185] have identified a number of small molecules that interfere with protein-protein interactions involving the Bcl-2, Bcl-xL and/or Mcl-1 BH3 binding grooves [10, 11, 186?89], thus mimicking the effects of sensitizer BH3-only proteins depicted in Fig. 1. For a small molecule to truly be a BH3 mimetic, its killing must depend on Bax and/or Bak, it must have a high affinity for at least one anti-apoptotic Bcl-2 family member, and it must induce cytotoxicity that correlates with binding to anti-apoptotic protein(s) [186]. Some compounds originally reported to be BH3 mimetics, e.g., BH3I class compounds, HA14-1, antimycin A, and purpurogallin, are no longer thought to kill in this manner because they exhibit poor binding to BH3 binding grooves or Bax/Bak-independent killing [186, 190, 191]. Other agents (Table 2) meet the criteria outlined above and have undergone preclinical and, in some cases, clinical testing. These include AT-101 [the R-(-) enantiomer of gossypol] [192?94]; the gossypol derivatives TW37 [192], apogossypol, and apogossypolone (ApoG2) [195, 196]; and obatoclax (GX15-070) [186, 197?99], although obatoclax also kills Bax/Bak-deficient cells [191, 200], perhaps because it inhibits the prosurvival kinase mTOR [201]. Of particular interest are Vasoactive Intestinal Peptide (human, rat, mouse, rabbit, canine, porcine) cost ABT-737 and its orally bioavailable derivative ABT-263 (navitoclax). These agents bind the BH3 binding grooves of Bcl-xL, Bcl-2, and Bcl-w [186, 191, 192, 202?04] to kill cells in a Bax- or Bak-dependent manner [191, 192]. Interestingly, their major toxicity, thrombocytopenia, also results from Bcl-xL inhibition [205, 206]. To avoid this side effect, the Bcl-2-selective derivative ABT-199 has been developed [207]. Cellular studies have shown that ABT-737, navitoclax and ABT-199 displace Bim from their identified anti-apoptotic binding partner(s), facilitating Baxmediated MOMP [203, 208, 209]. Priming of Bcl-2 with the activator Bim increases sensitivity to ABT-737, navitoclax and ABT-199, whereas Mcl-1 overexpression favors resistance [56, 191, 203, 208?10]. All of these observations are consistent with the proposed mode of action of these agents. 4.2 Clinical trials of BH3 mimeticsAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptIn view of the important role of Bcl-2 in the pathogenesis of lymphoid malignancies (see above), BH3 mimetics have been extensively tested in these disorders (reviewed in [211]). Early clinical testing revealed activity of navitoclax in CLL and non-.Reas recent studies suggest improved survival with tFL in the rituximab era [166, 183], raising the possibility that rituximab might partially counter the adverse impact of genomic changes leading to transformation. Thus, it will be important in the future to assess whether BCL2 mutation status correlates with outcome in FL treated with rituximabcontaining chemoimmunotherapy.Author Manuscript Author Manuscript Author Manuscript Author ManuscriptBiochim Biophys Acta. Author manuscript; available in PMC 2016 July 01.Correia et al.Page4. Targeting Bcl-2 as an anticancer strategy4.1 Small molecule inhibitors of Bcl-2 family proteins Because Bcl-2 overexpression contributes to the pathogenesis of various lymphoid neoplasms, particularly FL and CLL [17, 93, 94, 121], and possibly solid tumors [80], there has been substantial effort to develop Bcl-2 inhibitors as therapeutic agents. A combination of nuclear magnetic resonance-based binding assays and fluorescence polarization displacement assays [184, 185] have identified a number of small molecules that interfere with protein-protein interactions involving the Bcl-2, Bcl-xL and/or Mcl-1 BH3 binding grooves [10, 11, 186?89], thus mimicking the effects of sensitizer BH3-only proteins depicted in Fig. 1. For a small molecule to truly be a BH3 mimetic, its killing must depend on Bax and/or Bak, it must have a high affinity for at least one anti-apoptotic Bcl-2 family member, and it must induce cytotoxicity that correlates with binding to anti-apoptotic protein(s) [186]. Some compounds originally reported to be BH3 mimetics, e.g., BH3I class compounds, HA14-1, antimycin A, and purpurogallin, are no longer thought to kill in this manner because they exhibit poor binding to BH3 binding grooves or Bax/Bak-independent killing [186, 190, 191]. Other agents (Table 2) meet the criteria outlined above and have undergone preclinical and, in some cases, clinical testing. These include AT-101 [the R-(-) enantiomer of gossypol] [192?94]; the gossypol derivatives TW37 [192], apogossypol, and apogossypolone (ApoG2) [195, 196]; and obatoclax (GX15-070) [186, 197?99], although obatoclax also kills Bax/Bak-deficient cells [191, 200], perhaps because it inhibits the prosurvival kinase mTOR [201]. Of particular interest are ABT-737 and its orally bioavailable derivative ABT-263 (navitoclax). These agents bind the BH3 binding grooves of Bcl-xL, Bcl-2, and Bcl-w [186, 191, 192, 202?04] to kill cells in a Bax- or Bak-dependent manner [191, 192]. Interestingly, their major toxicity, thrombocytopenia, also results from Bcl-xL inhibition [205, 206]. To avoid this side effect, the Bcl-2-selective derivative ABT-199 has been developed [207]. Cellular studies have shown that ABT-737, navitoclax and ABT-199 displace Bim from their identified anti-apoptotic binding partner(s), facilitating Baxmediated MOMP [203, 208, 209]. Priming of Bcl-2 with the activator Bim increases sensitivity to ABT-737, navitoclax and ABT-199, whereas Mcl-1 overexpression favors resistance [56, 191, 203, 208?10]. All of these observations are consistent with the proposed mode of action of these agents. 4.2 Clinical trials of BH3 mimeticsAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptIn view of the important role of Bcl-2 in the pathogenesis of lymphoid malignancies (see above), BH3 mimetics have been extensively tested in these disorders (reviewed in [211]). Early clinical testing revealed activity of navitoclax in CLL and non-.
