BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins

Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 05/2010; 53(10):4166-76. DOI: 10.1021/jm1001265
Source: PubMed


In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.31, 0.32, 0.20, and 0.62 microM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 microM, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.

Download full-text


Available from: William Placzek, Feb 10, 2014
  • Source
    • "anti-tumor chemotherapeutic agents over the life span of the patient may be necessary to provide enduring clinical responses (Di Lorenzo and De Placido, 2006; Damber and Aus, 2008). Previous studies demonstrated that BI-97C1 (Sabutoclax), which is a pure optical derivative of Apogossypol (Wei et al., 2010), has significant activity as a single agent against PC cells in vitro and in vivo in nude mouse xenograft studies. Apogossypol derivatives antagonize the anti-apoptotic Bcl-2 family members including Bcl-2 and myeloid cell leukemia-1 (Mcl-1) (Wei et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Few options are available for treating patients with advanced prostate cancer (PC). As PC is a slow growing disease and accessible by ultrasound, gene therapy could provide a viable option for this neoplasm. Conditionally replication-competent adenoviruses (CRCAs) represent potentially useful reagents for treating prostate cancer (PC). We previously constructed a CRCA, Cancer Terminator Virus (CTV), which showed efficacy both in vitro and in vivo for PC. The CTV was generated on a serotype 5-background (Ad.5-CTV) with infectivity depending on Coxsackie-Adenovirus Receptors (CARs). CARs are frequently reduced in many tumor types, including PCs thereby limiting effective Ad-mediated therapy. Using serotype chimerism, a novel CTV (Ad.5/3-CTV) was created by replacing the Ad.5 fiber knob with the Ad.3 fiber knob thereby facilitating infection in a CAR-independent manner. We evaluated Ad.5/3-CTV in comparison with Ad.5-CTV in low CAR human PC cells, demonstrating higher efficiency in inhibiting cell viability in vitro. Moreover, Ad.5/3-CTV potently suppressed in vivo tumor growth in a nude mouse xenograft model and in a spontaneously induced PC that develops in Hi-myc transgenic mice. Considering the significant responses in a Phase I clinical trial of a non-replicating Ad.5-mda-7 in advanced cancers, Ad.5/3-CTV may exert improved therapeutic benefit in a clinical setting. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 07/2013; 229(1). DOI:10.1002/jcp.24408 · 3.84 Impact Factor
  • Source
    • "Failure of surveillance/maintanence over cell fate decision could result in malignant transformation. Evasion from apoptosis as a hallmark of cancerous cells may involve dysregulation of Bcl-2 family proteins as evidence indicates that a wide variety of solid and hematopoietic tumors rely on elevated antiapoptotic Bcl-2 protein expression for survival [33]–[36]. In this view, inspection of cellular levels and activation statuses of pro- and antiapoptotic Bcl-2 proteins may provide valuable clues about anticancer drug action.As a result, interest in Bcl-2 family regulation by putative or established chemotherapetics has been increasing. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pramanicin (PMC) is an antifungal agent that was previously demonstrated to exhibit antiangiogenic and anticancer properties in a few in vitro studies. We initially screened a number of PMC analogs for their cytotoxic effects on HCT116 human colon cancer cells. PMC-A, the analog with the most potent antiproliferative effect was chosen to further interrogate the underlying mechanism of action. PMC-A led to apoptosis through activation of caspase-9 and -3. The apoptotic nature of cell death was confirmed by abrogation of cell death with pretreatment with specific caspase inhibitors. Stress-related MAPKs JNK and p38 were both activated concomittantly with the intrinsic apoptotic pathway. Moreover, pharmacological inhibition of p38 proved to attenuate the cell death induction while pretreatment with JNK inhibitor did not exhibit a protective effect. Resistance of Bax -/- cells and the protective nature of caspase-9 inhibition indicate that mitochondria play a central role in PMC-A induced apoptosis. Early post-exposure elevation of cellular Bim and Bax was followed by a marginal Bcl-2 depletion and Bid cleavage. Further analysis revealed that Bcl-2 downregulation occurs at the mRNA level and is critical to mediate PMC-A induced apoptosis, as ectopic Bcl-2 expression substantially spared the cells from death. Conversely, forced expression of Bim proved to significantly increase cell death. In addition, analyses of p53-/- cells demonstrated that Bcl-2/Bim/Bax modulation and MAPK activations take place independently of p53 expression. Taken together, p53-independent transcriptional Bcl-2 downregulation and p38 signaling appear to be the key modulatory events in PMC-A induced apoptosis.
    PLoS ONE 02/2013; 8(2):e56369. DOI:10.1371/journal.pone.0056369 · 3.23 Impact Factor
  • Source
    • "Mortality from PCa most commonly results from the resistance to chemotherapy with docetaxel. To evaluate the ability of the panactive Bcl-2 inhibitor Sabutoclax to synergize with docetaxel for the treatment of human PCa, we used the Chou-Talalay method for synergy analysis [28] [40]. This model is able to take into account the nonuniform dose-response curves that we had previously observed in single-agent dosing experiments [30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptosis. Here we report the development of a novel transgenic mouse model that spontaneously develops prostatic intraepithelial neoplasia and adenocarcinoma by the inducible, conditional knockout of transforming growth factor β receptor type II in stromal fibroblastic cells (Tgfbr2(ColTKO)). The Tgfbr2(ColTKO) prostate epithelia demonstrated down-regulation of luminal and basal differentiation markers, as well as Pten expression and up-regulation of Mcl-1. However, unlike in men, Tgfbr2(ColTKO) prostates exhibited no regression acutely after castration. The administration of Sabutoclax (BI-97C1), a pan-active Bcl-2 protein family antagonist mediated apoptosis in castrate-resistant PCa cells of Tgfbr2(ColTKO) mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2(ColTKO) and wild-type mice. Sabutoclax was able to block c-Met activation, a critical axis in PCa metastatic progression. Further, Sabutoclax synergistically sensitized PC-3 cells to the cytotoxic effects of docetaxel (Taxotere). Together, these data suggest that Sabutoclax inhibits castrate-resistant PCa alone at the primary and bone metastatic site as well as support sensitivity to docetaxel treatment.
    Neoplasia (New York, N.Y.) 07/2012; 14(7):656-65. DOI:10.1593/neo.12640 · 4.25 Impact Factor
Show more