Structure-Based Design of Potent Small-Molecule Inhibitors of Anti-Apoptotic Bcl-2 Proteins

Wang, Guoping; Nikolovska‐Coleska, Zaneta; Yang, Chao; Wang, Renxiao; Tang, Guozhi; Guo, Jie; Shangary, Sanjeev; Qiu, Su; Gao, Wei; Yang, Dajun; Meagher, Jennifer L.; Stuckey, Jeanne A.; Krajewski, Krzysztof; Jiang, Sheng; Roller, Peter P.; Abaan, Hatice Özel; Tomita, York; Wang, Shaomeng

doi:10.1021/jm060460o

Cited by 271 publications

(277 citation statements)

References 16 publications

(48 reference statements)

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“…23 To estimate the binding affinities of (À)-gossypol for individual Bcl-2 family members, competition fluorescence polarization assays were performed with a fluorescently tagged Bid BH3 peptide. 24 K i values were determined instead of binding concentrations, as they more directly measure the inhibitory capacity of (À)-gossypol. As shown in Figure 2a, the K i values of (À)-gossypol for Mcl-1, Bcl-2 and Bcl-x L were 180, 320 and 480 nM, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…(À)-Gossypol was synthesized as described previously. 24 For oral dosing, lyophilized (À)-gossypol was resuspended in 100% ethanol, and subsequently diluted in sterile water to 10% ethanol, for a working concentration of 1.5 mg/ml.…”

Section: Figurementioning

confidence: 99%

“…Gossypol is interesting because, to our knowledge, it is the only bioavailable compound able to bind Mcl-1 23 that is in being tested in phase II clinical trials. 24 In the context of melanoma, gossypol has long been known to kill melanoma cells more efficaciously than normal melanocytes. [25][26][27] However, the mechanism(s) underlying this selectivity is unclear.…”

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confidence: 99%

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Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

et al. 2007

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Melanoma cells depend on sustained proteasomal function for survival. However, bortezomib, the first proteasome inhibitor in clinical use, is not sufficient to improve the poor prognosis of metastatic melanoma patients. Since the proteasome is also expressed in all normal cell compartments, it is unclear how to enhance the efficacy of bortezomib without exacerbating secondary toxicities. Here, we present pharmacological and genetic analyses of mechanisms of resistance to proteasome inhibition. We focused on Bcl-2, Bcl-x L and Mcl-1 as main antiapoptotic factors associated with melanoma progression. Despite an efficient blockage of the proteasome, bortezomib could not counteract the intrinsically high levels of Bcl-2 and Bcl-x L in melanoma cells. Moreover, Mcl-1 was only downregulated at late time points after treatment. Based on these results, a combination treatment including (À)-gossypol, an inhibitor of Mcl-1/Bcl-2/Bcl-x L , was designed and proven effective in vivo. Using a specific RNA interference approach, the survival of bortezomib-treated melanoma cells was found to rely primarily on Mcl-1, and to a lesser extent on Bcl-x L (but not on Bcl-2). Importantly, neither Mcl-1 nor Bcl-x L inactivation affected the viability of normal melanocytes. This hierarchical requirement of Bcl-2 family members for the maintenance of normal and malignant cells offers a therapeutic window to overcome melanoma chemoresistance in a tumor cell-selective manner.

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Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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confidence: 99%

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Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

et al. 2007

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“…N is used to treat lymphoid malignancies, small‐cell lung cancer, and chronic lymphocytic leukemia (Wendt, 2008; Vogler et al ., 2009; Billard, 2013). T is being investigated for treating certain types of cancer (Wang et al ., 2006). Also like D and Q, N and T have multiple targets.…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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“…6 (−)-Gossypol is currently in Phase II clinical trials and displays single-agent antitumor activity in patients with advanced malignancies. 7 The removal or mask of aldehyde groups has been shown to significantly reduce the toxicity of gossypol in humans. 8 As such, a variety of gossypol derivatives has been developed, including gossypol lactones, 9 gossypol nitriles, 5 gossypolone, 10 modification of the main structure of naphthalene, 7,11 etc.…”

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confidence: 99%

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Yue

et al. 2016

ACS Med. Chem. Lett.

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A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins. KEYWORDS: Gossypol Schiff bases, linear amino acid esters, antiapoptotic proteins N atural polyphenols have received considerable attention because of their biological activity. 1 Gossypol, a polyphenol that is isolated from cotton seeds, has long been investigated for antitumor activity in addition to the reported antiviral (such as anti-HIV 2 and anti-H 5 N 1 3 ), antifungal, 4 and antimalarial 5 activity as well as the inhibition of trypanosome T. brucei activity. 6 (−)-Gossypol is currently in Phase II clinical trials and displays single-agent antitumor activity in patients with advanced malignancies. 7 The removal or mask of aldehyde groups has been shown to significantly reduce the toxicity of gossypol in humans. 8 As such, a variety of gossypol derivatives has been developed, including gossypol lactones, 9 gossypol nitriles, 5 gossypolone, 10 modification of the main structure of naphthalene, 7,11 etc. Among these, gossypol Schiff bases displayed widespread biological activities. The purpose of the introduction of the imine through the aldehyde was to reduce the toxicity of gossypol without a loss in the activity since the hydroxyl group appears to be essential for the activity in many cases. 12 However, from known results, the reported activities of aldehyde derived compounds, including gossypol Schiff bases, decreased dramatically compared with gossypol itself in terms of antitumor activity ( Figure 1A). 12−15 The antitumor activities of gossypol Schiff bases were improved slightly only when the framework of gossypol was changed into gossypolone ( Figure 1B). 15 The effects of the introduced substituents of gossypol Schiff bases on the antitumor activity were still ambiguous. As a matter of fact, an investigation of the mechanism of the gossypol Schiff bases was not pursued in these previous studies. On the other hand, studies have shown that gossypol may inhibit tumor cells by interacting with Bcl-2 family proteins, which are the central regulators of apoptosis (programmed cell-death). 16 The modulation of the antiapoptotic Bcl-2 family (Bcl-2 and ...

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Structure-Based Design of Potent Small-Molecule Inhibitors of Anti-Apoptotic Bcl-2 Proteins

Cited by 271 publications

References 16 publications

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

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