Author: Chen, Xiu-Cai ; Tan, Jia-Heng ; Chen, Shuo-Bin ; Ou, Tian-Miao ; Wu, Tian-Ying ; Dai, Jing ; Dai, Le-Tian ; Li, Wen-Wei ; Huang, Zhi-Shu ; Tang, Gui-Xue

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.

01 Mar 2023·Journal of Biological Chemistry

Early-phase drug discovery of β-III-spectrin actin-binding modulators for treatment of spinocerebellar ataxia type 5

Article

Author: Avery, Adam W ; Keller, Amanda R ; Rebbeck, Robyn T ; Carter, Anna L ; Hays, Thomas S ; Atang, Alexandra E ; Denha, Sarah A ; Svensson, Bengt ; Thomas, David D ; Guhathakurta, Piyali

β-III-Spectrin is a key cytoskeletal protein that localizes to the soma and dendrites of cerebellar Purkinje cells and is required for dendritic arborization and signaling. A spinocerebellar ataxia type 5 L253P mutation in the cytoskeletal protein β-III-spectrin causes high-affinity actin binding. Previously we reported a cell-based fluorescence assay for identification of small-molecule actin-binding modulators of the L253P mutant β-III-spectrin. Here we describe a complementary, in vitro, fluorescence resonance energy transfer (FRET) assay that uses purified L253P β-III-spectrin actin-binding domain (ABD) and F-actin. To validate the assay for high-throughput compatibility, we first confirmed that our 50% FRET signal was responsive to swinholide A, an actin-severing compound, and that this yielded excellent assay quality with a Z' value > 0.77. Second, we screened a 2684-compound library of US Food and Drug Administration-approved drugs. Importantly, the screening identified numerous compounds that decreased FRET between fluorescently labeled L253P ABD and F-actin. The activity and target of multiple Hit compounds were confirmed in orthologous cosedimentation actin-binding assays. Through future medicinal chemistry, the Hit compounds can potentially be developed into a spinocerebellar ataxia type 5-specific therapeutic. Furthermore, our validated FRET-based in vitro high-throughput screening platform is poised for screening large compound libraries for β-III-spectrin ABD modulators.

01 Dec 2022·Journal of Thermal Analysis and Calorimetry

Investigating the thermal behavior of doxycycline and meclocycline

Author: Ferreira, Ana P. G. ; Cavalheiro, Eder T. G. ; de Freitas, Jonatha

The thermal behavior of the antibiotics doxycycline (Dox) and meclocycline (Meclo) in the monohydrate and sulfosalicylate forms was investigated by TG/DTG, TG/DTA, DSC and TG-FTIR.Dox decomposed in three steps after its melting at 174°C, with no evidence of crystallization on cooling.According to thermogravimetry associated with evolved gas anal., it was suggested that decomposition begins with the release of: water, isocyanic acid, dimethylamine, as well as carbon dioxide and ammonia, resulting from the decomposition of isocyanic acid.At 535°C carbon monoxide, methane and water were identified in gaseous phase.Meclo decomposed in two steps and did not presented melting and crystallization events.The gases released by Meclo during thermal decomposition were sulfur dioxide (from sulfosalicylate), carbon dioxide, isocyanic acid, carbon monoxide and ammonia.A mechanism for the thermal degradation of both antibiotics in nitrogen, has been proposed.

100 Deals associated with Meclocycline Sulfosalicylate

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D02477	-	D10AF04	DB13092

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Acne Vulgaris	-	-	-
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Indication	Highest Phase	Country/Location	Organization	Date
Stomatitis	Phase 1	United States	Coserics LLC	-
Stomatitis	Phase 1	India	Coserics LLC	-

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