Category: 5291-32-7

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USE OF ERIBULIN AND 3-QUINUCLIDINONE DERIVATIVES IN THE TREATMENT OF CANCER

The invention features methods for treating and preventing cancer (e.g., a p53-mutated cancer) in a patient in need thereof by administering eribulin (e.g., eribulin mesylate) in combination with a 3-quinuclidinone derivative (e.g., PRIMA-1 or PRIMA-1MET).

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Quinuclidine – Wikipedia,
Quinuclidine | C7H164N | ChemSpider

Children learn through play, and they learn more than adults might expect. Science experiments are a great way to spark their curiosity, get their minds active, and encourage them to do something that doesn¡¯t involve a screen. 5291-32-7, C10H17NO3. A document type is Article, introducing its new discovery., COA of Formula: C10H17NO3

SLMP53-2 restoreswild-type-like function to mutant p53 through hsp70: Promising activity in hepatocellular carcinoma

Half of human cancers harbor TP53 mutations that render p53 inactive as a tumor suppressor. In these cancers, reactivation of mutant p53 (mutp53) through restoration of wild-type-like function constitutes a valuable anticancer therapeutic strategy. In order to search for mutp53 reactivators, a small library of tryptophanol-derived oxazoloisoindolinones was synthesized and the potential of these compounds as mutp53 reactivators and anticancer agents was investigated in human tumor cells and xenograft mouse models. By analysis of their anti-proliferative effect on a panel of p53-null NCI-H1299 tumor cells ectopically expressing highly prevalent mutp53, the compound SLMP53-2 was selected based on its potential reactivation of multiple structuralmutp53. In mutp53-Y220C-expressing hepatocellular carcinoma (HCC) cells, SLMP53-2-induced growth inhibition was mediated by cell cycle arrest, apoptosis, and endoplasmic reticulum stress response. In these cells, SLMP53-2 restored wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the heat shock protein 70 (Hsp70), leading to the reestablishment of p53 transcriptional activity. Additionally, SLMP53-2 displayed synergistic effect with sorafenib, the only approved therapy for advanced HCC. Notably, it exhibited potent antitumor activity in human HCC xenograft mouse models with a favorable toxicological profile. Collectively, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity, particularly against HCC.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H169N | ChemSpider

An article , which mentions 5291-32-7, molecular formula is C10H17NO3. The compound – APR-246 played an important role in people’s production and life., Formula: C10H17NO3

Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1

TP53 mutations frequently occur in head and neck squamous cell carcinoma (HNSCC) patients without human papillomavirus infection. The recurrence rate for these patients is distinctly high. It has been actively explored to identify agents that target TP53 mutations and restore wild-type (WT) TP53 activities in HNSCC. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analogue PRIMA-1Met (also called APR-246) were found to be able to reestablish the DNA-binding activity of p53 mutants and reinstate the functions of WT p53. Herein we report that piperlongumine (PL), an alkaloid isolated from Piper longum L., synergizes with APR-246 to selectively induce apoptosis and autophagic cell death in HNSCC cells, whereas primary and immortalized mouse embryonic fibroblasts and spontaneously immortalized non-tumorigenic human skin keratinocytes (HaCat) are spared from the damage by the co-treatment. Interestingly, PL-sensitized HNSCC cells to APR-246 are TP53 mutation-independent. Instead, we demonstrated that glutathione S-transferase pi 1 (GSTP1), a GST family member that catalyzes the conjugation of GSH with electrophilic compounds to fulfill its detoxification function, is highly expressed in HNSCC tissues. Administration of PL and APR-246 significantly suppresses GSTP1 activity, resulting in the accumulation of ROS, depletion of GSH, elevation of GSSG, and DNA damage. Ectopic expression of GSTP1 or pre-treatment with antioxidant N-acetyl-l-cysteine (NAC) abrogates the ROS elevation and decreases DNA damage, apoptosis, and autophagic cell death prompted by PL/APR-246. In addition, administration of PL and APR-246 impedes UMSCC10A xenograft tumor growth in SCID mice. Taken together, our data suggest that HNSCC cells are selectively sensitive to the combination of PL and APR-246 due to a remarkably synergistic effect of the co-treatment in the induction of ROS by suppression of GSTP1.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H170N | ChemSpider

One of the major reasons for studying chemical kinetics is to use measurements of the macroscopic properties of a system, Computed Properties of C10H17NO3, such as the rate of change in the concentration of reactants or products with time.In a article, authors is Schrader, mentioned the application of 5291-32-7, Name is APR-246, molecular formula is C10H17NO3

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

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Quinuclidine | C7H175N | ChemSpider

Chemistry is an experimental science, and the best way to enjoy it and learn about it is performing experiments. SDS of cas: 5291-32-7. Introducing a new discovery about 5291-32-7, Name is APR-246

COMBINATION CANCER THERAPIES

Drug combinations of a heteroarotinoid (e.g., SHetA2), and an Azabicyclooctan-3-one derivative (e.g., PRIMA-1 or PRIMAMET) and/or, a CDK4/6 inhibitor (e.g., Palbociclib, Abemaciclib, or Ribociclib), which are synergistically-effective as anti-cancer treatments, and kits and methods of use of such drug combinations.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H162N | ChemSpider

Application of 5291-32-7, The reaction rate of a catalyzed reaction is faster than the reaction rate of the uncatalyzed reaction at the same temperature.5291-32-7, Name is APR-246, molecular formula is C10H17NO3. In a Patent£¬once mentioned of 5291-32-7

METHODS FOR MODULATING CHEMOTHERAPEUTIC CYTOTOXICITY

Disclosed herein are methods of reducing cytotoxicity of a chemotherapeutic agent to non-cancer cells by administering to a subject with cancer an effective amount of an agent that inhibits CD47 signaling and a chemotherapeutic agent. Example disclosed methods reduce cardiotoxicity of a chemotherapeutic agent. Also disclosed are methods of increasing cytotoxicity of a chemotherapeutic agent in cancer cells by administering to a subject with a tumor an effective amount of an agent that inhibits CD47 signaling and a chemotherapeutic agent. In some embodiments, the inhibitor of CD47 signaling is administered to the subject before, during, or after the administration of the chemotherapeutic agent.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H167N | ChemSpider

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APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase

The low-molecular-weight compound APR-246 (PRIMA-1MET) restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. We show here that APR-246 also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. APR-246 inhibited both recombinant TrxR1 in vitro and TrxR1 in cells. A Sec-to-Cys mutant of TrxR1 was not inhibited by APR-246, suggesting targeting of the selenocysteine residue in wild-type TrxR1. Preheated APR-246 and its conversion product methylene quinuclidinone (MQ) were much more efficient TrxR1 inhibitors than APR-246 itself, indicating that MQ is the active compound responsible for TrxR1 enzyme inhibition. TrxR1 inhibited by MQ was still functional as a pro-oxidant NADPH oxidase. Knockdown of TrxR1 caused a partial and reproducible attenuation of APR-246- induced tumor cell death independently of p53 status. Cellular TrxR1 activity was also inhibited by APR-246 irrespective of p53 status. We show that APR-246 can directly affect cellular redox status via targeting of TrxR1. Our findings provide an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H173N | ChemSpider

Related Products of 5291-32-7, Because a catalyst decreases the height of the energy barrier, its presence increases the reaction rates of both the forward and the reverse reactions by the same amount.5291-32-7,APR-246. In a Patent£¬once mentioned of 5291-32-7

Aqueous solution comprising 3-quinuclidinones for the treatment of hyperproliferative, autoimmune and heart disease

no abstract published

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Quinuclidine – Wikipedia,
Quinuclidine | C7H163N | ChemSpider

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Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells

NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin (TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mutant p53-repressed target displaying opposite effects. A gene signature of NRF2 targets activated by mutant p53 shows a significant association with bad overall prognosis and with mutant p53 status in breast cancer patients. Concomitant inhibition of thioredoxin system with Auranofin and of mutant p53 with APR-246 synergizes in killing cancer cells expressing p53 gain-of-function mutants.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H172N | ChemSpider

One of the major reasons for studying chemical kinetics is to use measurements of the macroscopic properties of a system, Quality Control of APR-246, such as the rate of change in the concentration of reactants or products with time.In a article, mentioned the application of 5291-32-7, Name is APR-246, molecular formula is C10H17NO3

The benefit of reactivating p53 under MAPK inhibition on the efficacy of radiotherapy in melanoma

Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1Met) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1Met caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration.

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Quinuclidine – Wikipedia,
Quinuclidine | C7H171N | ChemSpider