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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 181 records · Page 10
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells

Highlights: • Authentic squamous cell carcinoma (SqCC) cell lines of the lung are sparse. • HARA lung SqCC cells depend highly on MCL1 for survival in vitro and in vivo. • MCL1-silenced HARA cells decline in number upon docetaxel (DTX) exposure. • High MCL1 mRNA expression is linked with shorter survival in lung SqCC patients. • MCL1 depletion + DTX is highly effective against Detroit 562 pharyngeal SqCC cells. MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan–Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available “lung SqCC cell lines”, with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1)Inhibitors that Demonstrate Potent Cellular Efficacy and In Vivo Activity in a Mouse Solid Tumor Xenograft Model

Abstract The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.

Pharmacology & Pharmacy↗
DOE OSTI2022

Efficacy of Stabilizing Calcium Battery Electrolytes through Salt-Directed Coordination Change

Achieving practical, high-energy-density calcium batteries requires controlling the stability of Ca 2+ electrolytes during calcium metal cycling. Because of the highly reactive nature of calcium, most typical electrolyte constituents are unstable, leading to electrode passivation and low Coulombic efficiency. Among various commercially available salts, calcium bis(trifluoromethylsulfonyl)imide (Ca(TFSI) 2 ) is attractive because of its oxidative stability and high solubility in a variety of solvents. However, this salt does not allow for calcium metal plating, and it has been proposed that TFSI – instability induced by Ca 2+ coordination is to blame. In this work, we test the ability of strongly coordinating Ca 2+ cosalts such as halides and borohydrides to displace TFSI – from the first coordination shell of Ca 2+ and thereby stabilize TFSI-based electrolytes to enable calcium plating. Through spectroscopic analysis, we find that the effectiveness of these cosalts at displacing the TFSI – anion is dependent on the solvent’s coordination strength toward Ca 2+ . Surprisingly, electrochemical calcium deposition behavior is not correlated to the population of bound or free TFSI – . Instead, the nature of the coordination interaction between Ca 2+ and the cosalt anion is more important for determining stability. Our findings indicate that TFSI – anions are inherently unstable during calcium deposition even in the nominally free state. Furthermore, strategies aimed at eliminating the interactions of these anions with the electrode surface via interface/interphase design are required.

25 ENERGY STORAGE↗