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2013年12月8日日曜日

Rhodanine Class of Compounds as Inhibitors of Protein Reductase

Enoyl acyl carrier protein (ACP) reductase, one of the enzymes of the type II fatty acid biosynthesis pathway, has been established as a promising target for the development of new drugs for malaria.

Here we present the discovery of a rhodanine (2-thioxothiazolidin-4-one) class of compounds as inhibitors of this enzyme using a combined approach of rational selection of compounds for screening, analogue search, docking studies, and lead optimization.

The most potent inhibitor exhibits an IC₅₀ of 35.6 nM against Plasmodium falciparum enoyl ACP reductase (PfENR) and inhibits growth of the parasite in red blood cell cultures at an IC₅₀ value of 750 nM.

Many more compounds of this class were found to inhibit PfENR at low nanomolar to low micromolar concentrations, expanding the scope for developing new antimalarial drugs. The structure−activity relationship of these rhodanine compounds is discussed.

2013年12月7日土曜日

Aminothiazole Secretase Inhibitors

A new γ-secretase modulators with an Aminothiazole core starting from a HTS hit is disclosed . Also, synthesis and SAR of this series are discussed.

These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production.

Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aβ42 peptide is shifted to smaller non-aggregating Aβ peptides. Compound 15 reduced brain Aβ42 in vivo in APPSwe transgenic mice at 30 mg/kg p.o.

Protein Phosphatase-Directed Therapeutics　２０１６

Approaches to Study Phosphatases

Sara Fahs^†, Pablo Lujan^†, and Maja Köhn^*^†

^† European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany

ACS Chem. Biol., 2016, 11 (11), pp 2944–2961

DOI: 10.1021/acschembio.6b00570

Publication Date (Web): October 4, 2016

*E-mail: koehn@embl.de.

ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract

Phosphatases play key roles in normal physiology and diseases. Studying phosphatases has been both essential and challenging, and the application of conventional genetic and biochemical methods has led to crucial but still limited understanding of their mechanisms, substrates, and exclusive functions within highly intricate networks. With the advances in technologies such as cellular imaging and molecular and chemical biology in terms of sensitive tools and methods, the phosphatase field has thrived in the past years and has set new insights for cell signaling studies and for therapeutic development. In this review, we give an overview of the existing interdisciplinary tools for phosphatases, give examples on how they have been applied to increase our understanding of these enzymes, and suggest how they—and other tools yet barely used in the phosphatase field—might be adapted to address future questions and challenges.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.6b00570.

Abbreviations, Glossary, and Supporting Table 1 (PDF)

View: ACS ActiveView PDF | PDF | PDF w/ Links | Full Text HTML

Related Content

Protein phosphatases have both protective and promoting roles in the etiology of diseases. A prominent example is the existence of oncogenic as well as tumor-suppressing protein phosphatases.

A few protein phosphatase activity modulators are already applied in therapies. These were however not developed in target-directed approaches, and the recent discovery of phosphatase involvement followed their application in therapy.

Nevertheless, these examples demonstrate that small molecules can be generated that modulate the activity of protein phosphatases and are beneficial for the treatment of protein phosphorylation diseases.

We describe here strategies for the development of activators and inhibitors of protein phosphatases and clarify some long-standing misconceptions concerning the druggability of these enzymes.

Recent developments suggest that it is feasible to design potent and selective protein phosphatase modulators with a therapeutic potential.

http://pubs.acs.org/doi/abs/10.1021/cb300597g?prevSearch=%2528ERK%2Binhibitor%2529%2Band%2B%255BAbstract%253A%2Bsmall%255D&searchHistoryKey=

Live & Let Dye: ERK Phosphorilation Inhibitors

Both small molecules 22 and 23 inhibited the proliferation
of several cancer cell lines, including HeLa cells with
IC50 values of around 15–20 mm, and A549 lung carcinoma cells
with IC50 values of 25 and 15 mm, respectively.

Given the finding that compound 22 binds directly to ERK2, the authors investigated the possible binding mode to the protein. The computational
screening applied at the onset of this research predicted
that 22 fits into the polar grove located between the
CD and ED sites on the ERK2 protein.

More specifically, 22 appears to make contacts with several amino acid residues between
Asp316/Asp319 of the CD domain and Thr157/Thr158
of the ED domain. In particular, as well as a possible cation–p
interaction between Arg133 and the phenyl ring of 22, several
hydrogen bonds were observed between 22 and Asp316 and
Asp319.

It is likely that the amino group of 22 (protonated at
physiological pH) is engaged in salt bridges with Asp316 and
Asp319. Indeed, as well as taking advantage of its facile functionalization
towards structure optimization,

we are currently investigating the significance of the primary amine of 22 by introducing a variety of chemical modifications to reduce the
number of polar N H bonds and to alter the basicity of the nitrogen
atom; these results shall be reported in due course.

2013年12月6日金曜日

Dynamin GTPase Inhibitory Activity: Rhodadyns

From Rhodanine To Dynamin I GTPase Inhibitors

Abstract Image

Six focused rhodanine-based libraries, 60 compounds in total,
were synthesized and evaluated as potential dynamin I GTPase inhibitors.

Twenty-six were more potent than the lead compound with 13 returning IC₅₀ values ≤10 μM, making the Rhodadyn series among the most active dynamin inhibitors reported.

Two analogues were highly effective at blocking receptor-mediated endocytosis: C10 and D10 with IC_50(RME) = 7.0 ± 2.2 and 5.9 ± 1.0 μM, respectively.

These compounds are equipotent with the best reported in-cell dynamin inhibitors.

http://pubs.acs.org/doi/abs/10.1021/ml200284s

Dynamin is required for clathrin-mediated endocytosis (CME).

Its GTPase activity is stimulated by phospholipid binding to its PH domain, which induces helical oligomerization.

We have designed a series of novel pyrimidine-based “Pyrimidyn” compounds that inhibit the lipid-stimulated GTPase activity of full length dynamin I and II with similar potency.

The most potent analogue, Pyrimidyn 7, has an IC₅₀ of 1.1 μM for

dynamin I and 1.8 μM for dynamin II, making it among the most potent dynamin inhibitors identified to date.

We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin.
The compound competitively inhibits both GTP and phospholipid interactions with dynamin I. While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby to target two distinct domains of dynamin.

Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals.

Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation.
This dual mode of action provides an important new tool for molecular dissection of dynamin’s role in endocytosis.

2013年11月23日土曜日

Rhodanine can Visualize Neurofibrillary Tangles

There is a high demand for the development of an imaging agent for neurofibrillary tangles (NFTs) detection in Alzheimer’s diagnosis.

A series of rhodanine-3-acetic acids was synthesized and evaluated for fluorescence imaging of NFTs in brain tissues of AD patients. Five out of seven probes have shown excellent binding affinity to NFTs over amyloid plaques in the Thiazine red R displacement assay.

However, the selectivity in this in vitro assay is not confirmed by the histopathological evaluation, which indicates significant differences in the binding sites in the assays.

Probe 6 showed binding affinity (IC₅₀ = 19 nM) to tau aggregates which is the highest among this series. Probes 2, 3, 4 and 5 display IC₅₀ values of lower than 100 nM to tau aggregates to displace Thiazine red R.

Evaluation of the cytotoxicity of these five probes with human liver carcinoma cells revealed that these compounds excert negligible cytotoxicity.

The in vivo studies with zebrafish embryos confirmed negligible cytotoxicity at 24 and 72 h post fertilization.

2013年11月7日木曜日

Cyanine Dyes Can Modulate tau Aggregation.

A structure−activity relationship for symmetrical cyanine inhibitors of human tau aggregation was elaborated using a filter trap assay.

Antagonist activity depended on cyanine heterocycle, polymethine bridge length, and the nature of meso- and N-substituents. One potent member of the series, 3,3′-diethyl-9-methylthiacarbocyanine iodide (compound 11), retained submicromolar potency and had calculated physical properties consistent with blood−brain barrier and cell membrane penetration.

Exposure of organotypic slices prepared from JNPL3 transgenic mice (which express human tau harboring the aggregation prone P301L tauopathy mutation) to compound 11 for one week revealed a biphasic dose response relationship. Low nanomolar concentrations decreased insoluble tau aggregates to half those observed in slices treated with vehicle alone.

In contrast, high concentrations (≥300 nM) augmented tau aggregation and produced abnormalities in tissue tubulin levels. These data suggest that certain symmetrical carbocyanine dyes can modulate tau aggregation in the slice biological model at concentrations well below those associated with toxicity.

http://pubs.acs.org/doi/abs/10.1021/jm900116d?prevSearch=N744&searchHistoryKey=

2013年11月6日水曜日

Tranilast Binds to Aβ Monomers and Promotes Aβ Fibrillation

AD may be a potential complication for tranilast usage in elderly patients.

Abstract Image

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer’s disease (AD), in which amyloid β-protein (Aβ) plays a key pathogenic role.

We used solution NMR to determine that tranilast binds to Aβ40 monomers with

300 μM affinity.

Remarkably, tranilast increases Aβ40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time.

Tranilast likely promotes fibrillation by shifting Aβ monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the Aβ–tranilast interaction.

These data suggest that AD may be a potential complication for tranilast usage in elderly patients.

http://pubs.acs.org/doi/abs/10.1021/bi400426t?prevSearch=tranilast&searchHistoryKey=

2013年10月25日金曜日

Novel Inhibitors of TGF Signaling

Annulated 1,4-Dihydropyridines Cardiomyogenic Compounds

as Novel Inhibitors of TGFβ Signaling

A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface.

Because this is an unprecedented mechanism of action, we explored the series’ structure–activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs.

We determined a pharmacophore and generated 1,4-DHPs with IC₅₀s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM).

Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (−) enantiomer.

This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.

http://pubs.acs.org/doi/abs/10.1021/jm301144g?prevSearch=TGF%25CE%25B2%2BInhibitor&searchHistoryKey=

2013年10月24日木曜日

Cyanine Dye N744 Inhibits Tau Fibrillization

Cyanine Dye N744 Inhibits Tau Fibrillization by Blocking Filament Extension: Implications for the Treatment of Tauopathic Neurodegenerative Diseases

2013年10月23日水曜日

Orally Bioavailable, Brain Penetrant Kinase 3 Inhibitor for Parkinsons D

Orally Bioavailable, Brain Penetrant Inhibitor of Mixed Lineage Kinase 3

Inhibition of mixed lineage kinase 3 (MLK3) is a potential strategy for treatment of Parkinson’s disease and HIV-1 associated neurocognitive disorders (HAND), requiring an inhibitor that can achieve significant brain concentration levels.

We report here URMC-099 (1) an orally bioavailable (F = 41%), potent (IC₅₀ = 14 nM) MLK3 inhibitor with excellent brain exposure in mouse PK models and minimal interference with key human CYP450 enzymes or hERG channels.

The compound inhibits LPS-induced TNFα release in microglial cells, HIV-1 Tat-induced release of cytokines in human monocytes and up-regulation of phospho-JNK in Tat-injected brains of mice. Compound 1 likely functions in HAND preclinical models by inhibiting multiple kinase pathways, including MLK3 and LRRK2 (IC₅₀ = 11 nM). We compare the kinase specificity and BBB penetration of 1 with CEP-1347 (2). Compound 1 is well tolerated, with excellent in vivo activity in HAND models, and is under investigation for further development.

Compounds for the Treatment of Neurodegenerative Diseases

A series of indoles with Biaryl Appendage

are claimed as molecules that inhibit tau phosphorylation.
This approach to neurodegenerative disease is of interest because of the hypothesized role for tau in neuronal cell death.

Tau is an intracellular protein that stabilizes microtubules and helps regulate their function, for example in cell division.

Test compounds were studied for their ability to inhibit tau phosphorylation or inhibit α-synuclein in animals and in cell culture.

Adventures in Kinase Inhibitor Design and Optimization

Through the Looking Glass: Adventures in Kinase Inhibitor Design and Optimization

Robert D. Clark *

Department of Life Sciences, Simulations Plus, Inc., 42505 10th Street West, Lancaster, California 93534, United States

J. Med. Chem., 2013, 56 (5), pp 1796–1798

DOI: 10.1021/jm400243u

Abstract

Developing a viable new drug candidate is difficult.

Developing one that is a small molecule kinase inhibitor that binds competitively with respect to ATP with superb selectivity is even more difficult, which makes the design and optimization work described by Jimenez et al. (J. Med. Chem., DOI: 10.1021/jm301465a) particularly remarkable.

They took a lead from a high-throughput screen against protein kinase C θ (PKCθ) through a series of optimization steps, culminating in the demonstration of in vivo activity in mice. Having identified and improved the hinge-binding “warhead” at one end of their lead molecule, they proceeded to use structure-based design tools to guide modification of the other end to enhance selectivity over a closely related isoform of the kinase. With that accomplished, they used a series of protection and deprotection maneuvers to modify the central portion of the series scaffold to further enhance potency against the target while also improving pharmacokinetic properties.

The project was a success at the preclinical level: oral administration of the ultimate analogue obtained was effective at suppressing interleukin-2 induction in mice.

2013年10月19日土曜日

Epigenetic Regulator I-BET762

Benzodiazepine & Benzoxazepine Inhibitors: 2013 JMC

Abstract Image

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2013年12月8日日曜日

Rhodanine Class of Compounds as Inhibitors of Protein Reductase

2013年12月7日土曜日

Aminothiazole Secretase Inhibitors

Protein Phosphatase-Directed Therapeutics　２０１６

Approaches to Study Phosphatases

Abstract

Supporting Information

PDF

Other ACS content by these authors:

Related Content:

Metrics

Protein phosphatases have both protective and promoting roles in the etiology of diseases. A prominent example is the existence of oncogenic as well as tumor-suppressing protein phosphatases.

A few protein phosphatase activity modulators are already applied in therapies. These were however not developed in target-directed approaches, and the recent discovery of phosphatase involvement followed their application in therapy.

Nevertheless, these examples demonstrate that small molecules can be generated that modulate the activity of protein phosphatases and are beneficial for the treatment of protein phosphorylation diseases.

We describe here strategies for the development of activators and inhibitors of protein phosphatases and clarify some long-standing misconceptions concerning the druggability of these enzymes.

Recent developments suggest that it is feasible to design potent and selective protein phosphatase modulators with a therapeutic potential.

Live & Let Dye: ERK Phosphorilation Inhibitors

2013年12月6日金曜日

Dynamin GTPase Inhibitory Activity: Rhodadyns

2013年11月23日土曜日

Rhodanine can Visualize Neurofibrillary Tangles

2013年11月7日木曜日

Cyanine Dyes Can Modulate tau Aggregation.

2013年11月6日水曜日

Tranilast Binds to Aβ Monomers and Promotes Aβ Fibrillation

2013年10月25日金曜日

Novel Inhibitors of TGF Signaling

2013年10月24日木曜日

Cyanine Dye N744 Inhibits Tau Fibrillization

2013年10月23日水曜日

Orally Bioavailable, Brain Penetrant Kinase 3 Inhibitor for Parkinsons D

Compounds for the Treatment of Neurodegenerative Diseases

Adventures in Kinase Inhibitor Design and Optimization

Through the Looking Glass: Adventures in Kinase Inhibitor Design and Optimization

Abstract

2013年10月19日土曜日

Epigenetic Regulator I-BET762