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[ CAS No. 148893-10-1 ] {[proInfo.proName]}

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Chemical Structure| 148893-10-1
Chemical Structure| 148893-10-1
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Dilday, Tinslee ; Abt, Melissa ; Ramos-Solis, Nicole , et al. DOI: PubMed ID:

Abstract: Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer. Rubicon has been established as a substrate of HUNK that is phosphorylated at (S) 92. Findings indicate that HUNK-mediated phosphorylation of Rubicon at S92 promotes both and tumorigenesis in HER2/neu+ breast cancer. HUNK inhibition prevents Rubicon S92 phosphorylation in HER2/neu+ breast cancer models and inhibits tumorigenesis. This study characterizes a downstream phosphorylation event as a measure of HUNK activity and identifies a selective HUNK inhibitor that has meaningful efficacy toward HER2+ breast cancer.

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Ganga Reddy Velma ; Megan S. Laham ; Cutler Lewandowski , et al. DOI: PubMed ID:

Abstract: Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer’s disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell_x005f_x0002_membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark pathology.

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Wilms, Gerrit ; Schofield, Kevin ; Maddern, Shayna , et al. DOI: PubMed ID:

Abstract: Small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development, and adaptive immune homeostasis. Herein, we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with ligands for the component cereblon (CRBN) to induce ubiquitination and subsequent proteasomal degradation of DYRK1A and DYRK1B. The lead compound (DYR684) promoted fast, efficient, potent, and selective degradation of DYRK1A in cell-based assays. Interestingly, an enzymatically inactive splicing variant of DYRK1B (p65) resisted degradation. Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Collectively, our results identify DYRKs as viable targets for PROTAC-mediated degradation and qualify DYR684 as a useful chemical probe for DYRK1A and DYRK1B.

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Zhao, Yue ; Lyu, Zhigang ; Prather, Benjamin , et al. DOI:

Abstract: Dysregulated sialic acid biosynthesis is characteristic of the onset and progression of human diseases including hormone-sensitive prostate cancer and breast cancer. The sialylated glycoconjugates involved in this process are therefore important targets for identification and functional studies. To date, one of the most common strategies is metabolic glycoengineering, which utilizes N-acetylmannosamine (ManNAc) analogues such as N-azidoacetylmannosamine (ManNAz) to hijack sialic acid biosynthesis and label the sialylated glycoconjugates with "click chemistry (CuAAC)" tags. Yet, current chemical modifications including those CuAAC-based alkyne/azide tags are still big in size, and the resulting steric hindrance perturbs the mannosamine and sialic acid derivatives' recognition and metabolism by enzymes involved in biosynthetic pathways. As a result, the peracetylated ManNAz has compromised incorporation to sialic acid substrates and manifests cellular growth inhibition and cytotoxicity. Herein, we show that the α-fluorinated peracetylated analogue ManN(F-Ac) displayed a satisfying safety profile in mammalian cell lines at concentrations as high as 500 μM. More importantly, aliphatic selenol-containing probes can efficiently displace α-fluorine in fluoroacetamide-containing substrates including ManN(F-Ac) at a neutral pH range (~7.2). The combined use of peracetylated ManN(F-Ac) and the dethiobiotin-selenol probe as the fluorine-selenol displacement reaction (FSeDR) toolkit allowed for successful metabolic labeling of sialoglycoproteins in multiple prostate and cancer cell lines, including PC-3 and MDA-MB-231. More sialoglycoproteins in these cell lines were demonstrated to be labeled by FSeDR compared with the traditional CuAAC approach. Lastly, with FSeDR-mediated metabolic labeling, we were able to probe the cellular expression level and spatial distribution of sialylated glycoconjugates during the progression of these hormone-sensitive cancer cells. Taken together, the promising results suggest the potential of the FSeDR strategy to efficiently and systematically identify and study sialic acid substrates and potentially empower metabolic engineering on a diverse set of glycosylated proteins that are vital for human diseases.

Keywords: metabolic engineering ; mannosamine ; sialic acid ; glycobiology ; fluorine displacement reaction ; selenium ; fluorine-selenol displacement reaction (FSeDR)

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Dawson, Miranda ; DOI:

Abstract: The brain is in continuous communication with the rest of the body. Nerves connect the peripheral and central nervous system, and complex vasculature networks selectively permit passage of small molecules with an exogenous origin into the brain parenchyma. Although brain-body interactions underpin a host of cognitive and physiological phenomena, they are often overlooked in studies of brain biology and mental function. We studied aspects of the interaction between brain and body using functional and molecular magnetic resonance imaging (MRI), in combination with other tools. In a first project, we examined properties of the blood-brain barrier (BBB). The BBB is a highly selective collection of endothelial cells and tight junction proteins that restrict passage of extracerebral substances from the blood vessels into the brain tissue. We disrupted and bypassed the BBB to deliver an MRI contrast agent and quantitatively assessed the resulting contrast dynamics. We discovered that individual brain regions display method-independent susceptibility to BBB disruption and washout, suggesting principles for calibrating drug delivery and understanding the propensity for chemical exchange across the BBB. We then used one of the wide-field brain delivery techniques to apply a novel contrast agent for the study of the cholinergic system, a neurochemical pathway important for motor control mechanisms in both the central and peripheral nervous systems. Kinetic modeling of probe distributions revealed intrinsic localization of cholinergic enzymes. Finally, we applied related neuroimaging tools to an animal model of substance abuse, a pathology for which brain-body interactions are particularly engaged but underappreciated. We designed a study to investigate the role of the insula, a cortical mediator of peripheral physiological signals, in responses to opioid exposure. With molecular imaging approaches, we show the insula shapes drug-dependent brain phenotypes and physiological responses during substance exposure and withdrawal. In all, this work serves as a demonstration of the power of quantitative neuroimaging methods for multifaceted investigation of brain and body relationships.

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Senevirathne, Priyangika Prasadini ;

Abstract: Reactive oxygen species are a group of highly reactive oxygen-containing entities that are important at a cellular level for multiple biological processes. Low concentrations of ROS can be beneficial as powerful signaling molecules in those biological processes, although excessive concentrations can promote high levels of DNA damage and a variety of diseases such as skin cancer. A newly identified intracellular ROS production source in skin cells is NADPH oxidases. Out of the NOX enzyme family, the NOX1 holoenzyme is most abundantly expressed in the human keratinocyte cells. UV radiation can trigger the activation of NOX1 isoforms which stimulate the assembling of member CYBA and the cytoplasmic protein NOXO1. Inhibition of these enzymes represents a catalytic approach toward reducing ROS for the prevention of ROS inducible diseases. Key disease states include melanoma induced by UV exposure. The first half of the dissertation focuses on investigating new small molecule inhibitors of a key NOX1 holoenzyme to address these challenges. We designed a series of molecules by optimizing the structure of diapocynin and evaluated by in-silico docking methods to determine the binding affinity with NOXO1 cytoplasmic protein (1WLP crystal structure). And have synthesized the series of target molecules for the structure-activity relationship studies. In the first section of the project, we discovered that inhibitor NOX_inh_5 was not cytotoxic, but instead improved the viability of human primary cells from UV exposure, decreased the cellular stress in human skin through the p53 pathway, and reduced the UV-induced DNA damage as monitored by quantification of cyclobutane dimer formation after UV exposure. Then, we characterized the inhibition potential of NOX_inh_5 by using an Isothermal calorimetric (ITC) binding assay and heteronuclear single quantum coherence (HSQC) technique and revealed that the candidate iii molecule can prevent the complex formation of NOXO1 and CYBA membrane protein. In the second section of the project, we did a structure-activity relationship study for the NOX_inh_5 small molecule to optimize the biological characteristics. The last section of the dissertation discussed the development of ROS sensible prodrug to combat the opioid overdose crisis. Here we used oxidative stress conditions caused by opioid overdose to activate the prodrug. Even though opioid antagonist naloxone has a high affinity to bind with opioid receptors to block opioid-induced activation, it is metabolically unstable and has a short half-life of around 33 min. We developed a peroxide-induced prodrug to overcome this issue that can release a steady stream of naloxone. This allows the concentration of naloxone to remain high for longer periods.

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Product Details of [ 148893-10-1 ]

CAS No. :148893-10-1 MDL No. :MFCD00274639
Formula : C10H15F6N6OP Boiling Point : -
Linear Structure Formula :- InChI Key :FKBFHOSFPRWJNV-UHFFFAOYSA-N
M.W : 380.23 Pubchem ID :6409673
Synonyms :

Calculated chemistry of [ 148893-10-1 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.4
Num. rotatable bonds : 3
Num. H-bond acceptors : 10.0
Num. H-bond donors : 0.0
Molar Refractivity : 76.82
TPSA : 80.74 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.42 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 4.5
Log Po/w (WLOGP) : 6.27
Log Po/w (MLOGP) : 2.45
Log Po/w (SILICOS-IT) : -2.36
Consensus Log Po/w : 2.17

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -5.11
Solubility : 0.00294 mg/ml ; 0.00000773 mol/l
Class : Moderately soluble
Log S (Ali) : -5.92
Solubility : 0.000461 mg/ml ; 0.00000121 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -1.67
Solubility : 8.13 mg/ml ; 0.0214 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.41

Safety of [ 148893-10-1 ]

Signal Word:Danger Class:4.1
Precautionary Statements:P210-P264-P271-P240-P261-P280-P305+P351+P338-P302+P352-P304+P340-P312-P362-P370+P378-P403+P233-P501 UN#:1325
Hazard Statements:H228-H315-H319-H335 Packing Group:Ⅱ
GHS Pictogram:
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