ML 239

ML239 is the best-in-class inhibitor of the breast cancer stem cells with an IC₅₀ = 1.16 µM. [1]

ML239 was a selective inhibitor an IC₅₀= 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. Five genes (ATP6V0C, PKM2, PPDPF, RPL23, and SERINC2) were differentially regulated in HMLE_sh_GFP after treatment with ML239. 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. ML239 was selectively toxic toward another CSC-like cell line, HMLE_Twist, and the breast cancer line, MDA-MB-231. Similar to the results observed in the HMLE_sh_ECad cell line, ML239 was potently toxic, inhibiting HMLE_Twist with an IC₅₀ ~0.1 µM. ML239 displayed potent toxicity (IC₅₀ = 2.81 µM) to the breast carcinoma cell line, MDA-MB-231 [1]. ML239 also alters the expression of genes in the NF-κB, MAPK and inflammatory cytokine pathways.

Reference:

1.Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells. J Biomol Screen. 2012 Oct;17(9):1204-10. Epub 2012 Aug 30.

Rapid Analysis of 239,238Pu, 241Am, and 90Sr for Nasal Smear Samples in Radiation Emergency and Evaluation of Intake Retention Fraction.[Pubmed:28350699]

Health Phys. 2017 May;112(5):451-457.

The efficiency of the nasal smear method was reviewed to perform a method of sample collection, analysis and initial dose estimation. The screening method of alpha-emitting radionuclides using chemical separation and alpha spectrometry was also studied. To rapidly conduct the appropriate response to victims, special monitoring for Pu, Am, and Sr using sequential analysis was established, and the method was successfully validated through participation in an international inter-comparison program. The duration of the analysis method was evaluated with regard to application in emergency situations because of its relatively rapid treatment and counting time. The intake retention fraction was calculated and evaluated to review the characteristics of each radionuclide in the anterior nasal passage of the extra-thoracic region. No large difference was observed among the four radionuclides. However, the values of the intake retention fraction were affected by age groups because of the different respiratory rates. The effects of the Y ingrowth and particle size were also discussed.

Case 239: Cerebrotendinous Xanthomatosis.[Pubmed:28218883]

Radiology. 2017 Mar;282(3):916-921.

History A 63-year-old man with learning difficulties presented to the Accident and Emergency Department with right ankle pain after an inversion injury and underwent plain radiography. The patient had developed normally until his teenage years, at which point he experienced cognitive regression. He experienced swallowing difficulties, tinnitus, and fecal incontinence, and he had undergone cataract surgery at the age of 20 years. He also had a small nodule on the volar surface of his right ring finger. Magnetic resonance (MR) imaging of the brain and the right ankle had been performed 3 years previously. Routine biochemistry (full blood count and renal function) results were normal. Total cholesterol level was 3.6 mmol/L (normal, <5.0 mmol/L). The patient had three siblings who had the same condition, with one having died in childhood.

Determination of (238)Pu, (239+240)Pu and (241)Am in air filters.[Pubmed:28250547]

J Radioanal Nucl Chem. 2017;311(2):1271-1276.

The aim of this work is to present the method for sequential plutonium and americium activity determination in air filters using chromatographic radionuclide separation and alpha spectrometry measurement. The developed method may be employed for the purposes of workplace monitoring and as an indicator of the need of introducing the individual monitoring as well as a useful complementation of individual monitoring. Basic parameters describing the developed method such as values of chemical recoveries and minimum detectable activities for plutonium and americium isotopes have been determined. Applied counting efficiency was obtained using Monte Carlo calculation method.

Phenotypic high-throughput screening elucidates target pathway in breast cancer stem cell-like cells.[Pubmed:22941295]

J Biomol Screen. 2012 Oct;17(9):1204-10.

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 microM 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-kappaB 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).

Identification of a selective small molecule inhibitor of breast cancer stem cells.[Pubmed:22503247]

Bioorg Med Chem Lett. 2012 May 15;22(10):3571-4.

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).