Author: Price, Edmund V ; Wagner, Bridget K ; Palmer, Michelle ; Bodycombe, Nicole E ; Li, Ava ; Munoz, Benito ; Shamji, Alykhan F ; Bittker, Joshua A ; Haber, Daniel A ; Hon, C Suk-Yee ; Adams, Drew J ; Javaid, Sarah ; Gill, Shubhroz ; Montgomery, Philip ; Soule, Christian K ; Alexander, Benjamin ; Seashore-Ludlow, Brinton ; Cheah, Jaime H ; Coletti, Matthew E ; Schreiber, Stuart L ; Rees, Matthew G ; Liefeld, Ted ; Clemons, Paul A ; Clish, Clary B ; Kotz, Joanne D ; Jones, Victor L ; Dančík, Vlado

Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.

01 Oct 2012·SLAS Discovery

Phenotypic High-Throughput Screening Elucidates Target Pathway in Breast Cancer Stem Cell–Like Cells

Article

Author: Partha P. Nag ; Michelle A. J. Palmer ; Leigh C. Carmody ; Jose R. Perez ; Andrew R. Germain ; Benito Muñoz ; Lynn VerPlank

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).

01 May 2012·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Piyush B. Gupta ; Lynn VerPlank ; Amal Ting ; Cristina Fernandez ; Partha P. Nag ; Yuxiong Feng ; Andrew R. Germain ; Barbara Morgan ; Sivaraman Dandapani ; Eric Steven Lander ; Leigh C. Carmody ; Erin Forbeck ; Timothy A. Lewis ; Stuart L. Schreiber ; Benito Munoz ; Jose R. Perez ; Michelle Palmer

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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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	The Broad Institute, Inc.	-

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