Identification of a selective small molecule inhibitor of breast cancer stem cells

Chemical Biology Platform and Probe Development Center, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 01/2012; 22(10):3571-4. DOI: 10.1016/j.bmcl.2012.01.035
Source: PubMed


A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).

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    ABSTRACT: Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC(50)= 1.18 µM against HMLE_sh_ECad, demonstrated a >23-fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-κB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s).
    Journal of Biomolecular Screening 08/2012; 17(9):1204-10. DOI:10.1177/1087057112458317 · 2.42 Impact Factor
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    ABSTRACT: The identification of so-called cancer stem cells (CSCs) has sustainably changed our views on cancer by adding hierarchical principles, where tumor cells emerge from a founder population similar to steady-state regenerative processes in normal tissues. The rare founder population of CSCs is thought to be responsible for the recurrence of treatment-resistant tumors and metastatic spread and thus has been declared as the number one target for the next generation of anti-cancer drugs. Here, we will review the state of the art in research on breast cancer stem cells (BCSCs), for which a huge amount of data has accumulated in the past few years. Initial studies have suggested that the CD44+/CD24- profile and epithelial-to-mesenchymal transition (EMT) are associated with BCSCs, which has resulted in the recent identification of first compounds with BCSC-eliminating properties. In this early phase, however, it remains mostly unclear, to which extent these new compounds may exert toxicity to normal stem cells, since a substantial part targets molecular pathways critical for normal stem cell function. Moreover, these new drugs often require combination with conventional chemotherapeutics potentially posing new challenges to nanomedicine in circumventing toxicity and enabling targeted delivery. Most recent data further suggests that normal breast cancer cells might be able to re-create BCSCs and that additional, yet undiscovered kinds of BCSCs may exist. This points to future escape mechanisms. As a consequence, another broad future field of nanomedicine might be finding new drugs via systematic screening approaches. Collectively, this area provides ample possibilities for both traditional and novel nanomedical approaches.
    European Journal of Nanomedicine 12/2012; 4(2-4). DOI:10.1515/ejnm-2012-0006
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    ABSTRACT: A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
    Bioorganic & medicinal chemistry letters 03/2013; 23(6):1834-8. DOI:10.1016/j.bmcl.2013.01.025 · 2.42 Impact Factor
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