Publications by authors named "Sergey Zozulya"

36 Publications

Exploration of the nitrogen heterocyclic periphery around the core of the advanced FFA1 agonist fasiglifam (TAK-875).

Arch Pharm (Weinheim) 2021 Apr 3;354(4):e2000275. Epub 2020 Dec 3.

Institute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russian Federation.

Three types of heterocyclic moieties-piperidines fused to a heteroaromatic moiety-were explored as potential periphery motifs for the pharmacophoric core of fasiglifam (TAK-875), with fasiglifam being the most advanced agonist of free fatty acid receptor 1, a promising target for therapeutic intervention in type 2 diabetes. Several observed structure-activity relationship trends were corroborated by in silico docking results. Balanced selection based on potency and Caco-2 permeability advanced six compounds to cellular efficacy tests (glucose-stimulated insulin secretion in rat insulinoma INS1E cells). This led to the nomination of compound 16a (LK1408, 3-[4-({4-[(3-{[(2-fluorobenzyl)oxy]methyl}-1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)methyl]benzyl}oxy)phenyl]propanoic acid hydrochloride) as the lead for further development.
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http://dx.doi.org/10.1002/ardp.202000275DOI Listing
April 2021

Small-Molecule Chemical Knockdown of MuRF1 in Melanoma Bearing Mice Attenuates Tumor Cachexia Associated Myopathy.

Cells 2020 10 11;9(10). Epub 2020 Oct 11.

Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany.

Patients with malignant tumors frequently suffer during disease progression from a syndrome referred to as cancer cachexia (CaCax): CaCax includes skeletal muscle atrophy and weakness, loss of bodyweight, and fat tissues. Currently, there are no FDA (Food and Drug Administration) approved treatments available for CaCax. Here, we studied skeletal muscle atrophy and dysfunction in a murine CaCax model by injecting B16F10 melanoma cells into mouse thighs and followed mice during melanoma outgrowth. Skeletal muscles developed progressive weakness as detected by wire hang tests (WHTs) during days 13-23. Individual muscles analyzed at day 24 had atrophy, mitochondrial dysfunction, augmented metabolic reactive oxygen species (ROS) stress, and a catabolically activated ubiquitin proteasome system (UPS), including upregulated MuRF1. Accordingly, we tested as an experimental intervention of recently identified small molecules, Myomed-205 and -946, that inhibit MuRF1 activity and MuRF1/MuRF2 expression. Results indicate that MuRF1 inhibitor fed attenuated induction of MuRF1 in tumor stressed muscles. In addition, the compounds augmented muscle performance in WHTs and attenuated muscle weight loss. Myomed-205 and -946 also rescued citrate synthase and complex-1 activities in tumor-stressed muscles, possibly suggesting that mitochondrial-metabolic and muscle wasting effects in this CaCax model are mechanistically connected. Inhibition of MuRF1 during tumor cachexia may represent a suitable strategy to attenuate skeletal muscle atrophy and dysfunction.
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http://dx.doi.org/10.3390/cells9102272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600862PMC
October 2020

Synthesis, biological evaluation, and modeling studies of 1,3-disubstituted cyclobutane-containing analogs of combretastatin A4.

J Mol Struct 2020 Jun 10;1210. Epub 2020 May 10.

Enamine Ltd. (www.enamine.net), Chervonotkatska Street 78, Kyiv 02094, Ukraine.

With the aim of circumventing the adverse /-isomerization of combretastatin A4 (CA4), a naturally occurring tumor-vascular disrupting agent, we designed novel CA4 analogs bearing 1,3-cyclobutane moiety instead of the -stilbene unit of the parent compound. The corresponding and cyclobutane-containing derivatives were prepared as pure diastereomers. The structure of the target compounds was confirmed by X-ray diffraction study. The title compounds were evaluated for their cytotoxic properties in human cancer cell lines HepG2 (hepatocarcinoma) and SK-N-DZ (neuroblastoma), and the overall activity was found in micromolar range. Molecular docking studies and molecular dynamics simulation within the colchicine binding site of tubulin were in good agreement with the obtained cytotoxicity data.
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http://dx.doi.org/10.1016/j.molstruc.2020.128025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351177PMC
June 2020

Exploring bulky natural and natural-like periphery in the design of p-(benzyloxy)phenylpropionic acid agonists of free fatty acid receptor 1 (GPR40).

Bioorg Chem 2020 06 8;99:103830. Epub 2020 Apr 8.

Saint Petersburg State University, Saint Petersburg 199034, Russian Federation. Electronic address:

Six derivatives of 3-phenylpropionic acid bearing various natural and natural-like, spatially defined peripheral motifs have been synthesized and evaluated in vitro for free fatty acid receptor 1 (FFA1) activation. Two frontrunner compounds (bearing a bornyl and cytosine groups) were evaluated in an oral glucose tolerance test in mice where both demonstrated the ability to sustain blood glucose levels following a glucose challenge. The bornyl compound displayed a somewhat superior, dose-dependent efficacy and, therefore, can be regarded as a lead compounds for further development as a therapeutic agent for type 2 diabetes mellitus. Its high affinity to FFA1 was rationalized by docking experiments.
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http://dx.doi.org/10.1016/j.bioorg.2020.103830DOI Listing
June 2020

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Sci Rep 2019 12 20;9(1):19585. Epub 2019 Dec 20.

Education Academy of Computational Life Sciences (ACLS), Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, 226-8501, Japan.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.
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http://dx.doi.org/10.1038/s41598-019-55069-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925144PMC
December 2019

Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry.

J Enzyme Inhib Med Chem 2020 Dec;35(1):306-310

Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (CA) delivered >100 hits that either caused, on their own, a significant thermal shift (Δ, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of CA II, IX and XII which were efficacious . Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.
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http://dx.doi.org/10.1080/14756366.2019.1698562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896451PMC
December 2020

Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement.

J Enzyme Inhib Med Chem 2020 Dec;35(1):165-171

Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (CA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].
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http://dx.doi.org/10.1080/14756366.2019.1693556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882446PMC
December 2020

Difluoro-Substituted Bicyclo[1.1.1]pentanes for Medicinal Chemistry: Design, Synthesis, and Characterization.

J Org Chem 2019 12 7;84(23):15106-15117. Epub 2019 Oct 7.

Enamine Ltd. , Chervonotkatska 78 , Kyiv 02094 , Ukraine.

A practical synthetic approach to the difluoro-substituted bicyclo[1.1.1]pentanes was developed. The key step was an addition of difluorocarbene (:CF) to electron-rich bicyclo[1.1.0]butanes by the CFTMS/NaI system. The obtained difluoro-bicyclo[1.1.1]pentanes are suggested to be used as saturated bioisosteres of benzene rings for the purpose of drug discovery projects.
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http://dx.doi.org/10.1021/acs.joc.9b01947DOI Listing
December 2019

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity.

J Org Chem 2018 12 6;83(23):14350-14361. Epub 2018 Nov 6.

Enamine, Ltd. , Chervonotkatska 78 , Kyiv 02094 , Ukraine (www.enamine.net).

A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.
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http://dx.doi.org/10.1021/acs.joc.8b02071DOI Listing
December 2018

(Chlorosulfonyl)benzenesulfonyl Fluorides-Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library.

ACS Comb Sci 2018 11 1;20(11):672-680. Epub 2018 Nov 1.

National Taras Shevchenko University of Kyiv, Volodymyrska Street 60 , Kyiv 01601 , Ukraine.

Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.
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http://dx.doi.org/10.1021/acscombsci.8b00130DOI Listing
November 2018

Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors.

Bioorg Med Chem 2018 07 9;26(12):3399-3405. Epub 2018 May 9.

Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine; National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine. Electronic address:

A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC = 1.9-7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.
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http://dx.doi.org/10.1016/j.bmc.2018.05.010DOI Listing
July 2018

Synthesis of Multifunctional Spirocyclic Azetidines and Their Application in Drug Discovery.

Chemistry 2018 Apr 15;24(21):5444-5449. Epub 2018 Feb 15.

Enamine Ltd./Bienta, Chervonotkatska 78, 02094, Kyiv, Ukraine.

The synthesis of multifunctional spirocycles was achieved from common cyclic carboxylic acids (cyclobutane carboxylate, cyclopentane carboxylate, l-proline, etc.). The whole sequence included only two chemical steps-synthesis of azetidinones, and reduction into azetidines. The obtained spirocyclic amino acids were incorporated into a structure of the known anesthetic drug Bupivacaine. The obtained analogues were more active and less toxic than the original drug. We believe that this discovery will lead to a wide use of spirocyclic building blocks in drug discovery in the near future.
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http://dx.doi.org/10.1002/chem.201800193DOI Listing
April 2018

Photochemical Synthesis of 2-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. Synthesis of 2,3-Ethanoproline.

J Org Chem 2018 02 16;83(3):1394-1401. Epub 2018 Jan 16.

Enamine Ltd ., Chervonotkatska 78, Kyiv 02094, Ukraine , www.enamine.net.

Intramolecular photochemical [2 + 2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes, advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of proline, 2,3-ethanoproline, was performed.
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http://dx.doi.org/10.1021/acs.joc.7b02910DOI Listing
February 2018

Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists.

Eur J Med Chem 2017 Nov 13;140:229-238. Epub 2017 Sep 13.

Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Northern Ireland, UK.

An earlier reported series of 1,2,4-thiadiazole-based agonists of FFA1 (GPR40) was evolved into two structurally distinct series of compounds. One of the series (structurally related to known FFA1 agonist GW9508) displayed low micromolar potency while the other (representing a truncated version of the earlier reported potent FFA1 agonists) was, surprisingly, found to be devoid of agonist potency. In silico docking of representative compounds into the crystal structure of FFA1 revealed possible structural grounds for the observed SAR.
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http://dx.doi.org/10.1016/j.ejmech.2017.09.019DOI Listing
November 2017

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes.

Sci Rep 2017 09 20;7(1):12038. Epub 2017 Sep 20.

Advanced Computational Drug Discovery Unit, Institute of Innovative Research, Tokyo Institute of Technology, J3-23 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.

We propose a new iterative screening contest method to identify target protein inhibitors. After conducting a compound screening contest in 2014, we report results acquired from a contest held in 2015 in this study. Our aims were to identify target enzyme inhibitors and to benchmark a variety of computer-aided drug discovery methods under identical experimental conditions. In both contests, we employed the tyrosine-protein kinase Yes as an example target protein. Participating groups virtually screened possible inhibitors from a library containing 2.4 million compounds. Compounds were ranked based on functional scores obtained using their respective methods, and the top 181 compounds from each group were selected. Our results from the 2015 contest show an improved hit rate when compared to results from the 2014 contest. In addition, we have successfully identified a statistically-warranted method for identifying target inhibitors. Quantitative analysis of the most successful method gave additional insights into important characteristics of the method used.
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http://dx.doi.org/10.1038/s41598-017-10275-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607274PMC
September 2017

Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery.

J Org Chem 2017 09 25;82(18):9627-9636. Epub 2017 Aug 25.

Department of Chemistry, National Taras Shevchenko University of Kyiv , Volodymyrska 64, Kyiv 01033, Ukraine.

We have developed a rapid two-step synthesis of substituted 3-azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectular [2+2]-photochemical cyclization.
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http://dx.doi.org/10.1021/acs.joc.7b01678DOI Listing
September 2017

Polar aromatic periphery increases agonist potency of spirocyclic free fatty acid receptor (GPR40) agonists inspired by LY2881835.

Eur J Med Chem 2017 Feb 4;127:357-368. Epub 2017 Jan 4.

Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

A series of spirocyclic compounds inspired by Eli Lilly's phase 1 antidiabetic FFA1 receptor agonist LY2881835 was designed to include polar aromatic periphery groups and explore a possibility of building additional contacts with the target near the agonist binding site. The frontrunner compound in the series (9i) was shown to be a potent (EC = 260 nM) FFA1 agonist with excellent aqueous (PBS) solubility and good Caco-2 permeability. The observed structure-activity relationships were rationalized by a docking study. The new series significantly expands the ligand landscape for the ongoing quest for new potent and more polar FFA1 agonists as fundamentally new class of therapeutic agents against type 2 diabetes mellitus.
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http://dx.doi.org/10.1016/j.ejmech.2017.01.005DOI Listing
February 2017

Novel FFA1 (GPR40) agonists containing spirocyclic periphery: polar azine periphery as a driver of potency.

J Enzyme Inhib Med Chem 2017 Dec 26;32(1):29-36. Epub 2016 Oct 26.

c Enamine Ltd. , Kyiv , Ukraine.

A series of nine compounds based on 3-[4-(benzyloxy)phenyl]propanoic acid core containing a 1-oxa-9-azaspiro[5.5]undecane periphery was designed, synthesized and evaluated as free fatty acid 1 (FFA1 or GPR40) agonists. The spirocyclic appendages included in these compounds were inspired by LY2881835, Eli Lilly's advanced drug candidate for type II diabetes mellitus that was in phase I clinical trials. These polar spirocyclic, fully saturated appendages (that are themselves uncharacteristic of the known FFA1 ligand space) were further decorated with diverse polar groups (such as basic heterocycles or secondary amides). To our surprise, while seven of nine compounds were found to be inactive (likely due to the decrease in lipophilicity, which is known to be detrimental to FFA1 ligand affinity), two compounds containing 2-pyridyloxy and 2-pyrimidinyloxy groups were found to have EC of 1.621 and 0.904 µM, respectively. This result is significant in the context of the worldwide quest for more polar FFA1 agonists, which would be devoid of liver toxicity effects earlier observed for a FFA1 agonist fasiglifam (TAk-875) in clinical studies.
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http://dx.doi.org/10.1080/14756366.2016.1230110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021034PMC
December 2017

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835.

Bioorg Med Chem 2016 11 3;24(21):5481-5494. Epub 2016 Sep 3.

Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC=55nM) was reached. Four lead compounds (EC range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.
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http://dx.doi.org/10.1016/j.bmc.2016.09.004DOI Listing
November 2016

Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold.

Bioorg Med Chem 2016 07 5;24(13):2954-2963. Epub 2016 May 5.

Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.
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http://dx.doi.org/10.1016/j.bmc.2016.04.065DOI Listing
July 2016

Direct Photocontrol of Peptidomimetics: An Alternative to Oxygen-Dependent Photodynamic Cancer Therapy.

Angew Chem Int Ed Engl 2016 04 30;55(18):5493-6. Epub 2016 Mar 30.

Institute of High Technologies (IHT), Taras Shevchenko National University of Kyiv (TSNUK), vul. Volodymyrska 60, 01601, Kyiv, Ukraine.

Conventional photodynamic treatment strategies are based on the principle of activating molecular oxygen in situ by light, mediated by a photosensitizer, which leads to the generation of reactive oxygen species and thereby causes cell death. A diarylethene-derived peptidomimetic is presented that is suitable for photodynamic cancer therapy without any involvement of oxygen. This light-sensitive molecule is not a mediator but is itself the cytotoxic agent. As a derivative of the cyclic amphiphilic peptide gramicidin S, the peptidomimetic exists in two thermally stable photoforms that are interconvertible by light of different wavelengths. The isomer generated by visible light shows much stronger toxicity against tumor cells than the UV-generated isomer. First in vivo applications are demonstrated on a tumor animal model to illustrate how the peptidomimetic can be administered in the less toxic form and then activated locally in a solid tumor by visible light.
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http://dx.doi.org/10.1002/anie.201600506DOI Listing
April 2016

Discovery of Strecker-type α-aminonitriles as a new class of human carbonic anhydrase inhibitors using differential scanning fluorimetry.

J Enzyme Inhib Med Chem 2016 Dec 16;31(6):1707-11. Epub 2016 Mar 16.

d Neurofarba Department, Universita degli Studi di Firenze , Florence , Italy.

A new type of carbonic anhydrase inhibitors was identified via differential scanning fluorimetry (DSF) screening. The compounds displayed interesting inhibition profile against human carbonic anhydrase isoforms I, II, IX and XII with an obvious selectivity displayed by one compound toward carbonic anhydrase (CA) IX, an established anti-cancer target. A hypothetical mechanism of inhibitory action by the Strecker-type α-aminonitriles has been proposed.
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http://dx.doi.org/10.3109/14756366.2016.1156676DOI Listing
December 2016

Novel agonists of free fatty acid receptor 1 (GPR40) based on 3-(1,3,4-thiadiazol-2-yl)propanoic acid scaffold.

J Enzyme Inhib Med Chem 2016 Dec 22;31(6):1404-10. Epub 2016 Feb 22.

c Enamine Ltd , 78 Chervonotkatska, Kyiv , Ukraine , and.

1,3,4-Thiadiazole was explored as a more polar, heterocyclic replacement for the phenyl ring in the 3-arylpropionic acid pharmacophore present in the majority of GPR40 agonists. Out of 13 compounds synthesized using a flexible, three-step protocol (involving no chromatographic purification), four compounds were confirmed to activate the target in micromolar concentration range. While the potency of the series should be subject of further optimization, the remarkable aqueous solubility and microsomal stability observed for the lead compound (8g) apparently attests to this new scaffold's high promise in the GPR40 agonist field.
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http://dx.doi.org/10.3109/14756366.2016.1142984DOI Listing
December 2016

Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40).

Bioorg Med Chem Lett 2015 Aug 12;25(16):3105-11. Epub 2015 Jun 12.

Institute of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation. Electronic address:

A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.018DOI Listing
August 2015

Design, synthesis, and characterization of SO2-containing azabicyclo[3.n.1]alkanes: promising building blocks for drug discovery.

Org Lett 2015 Apr 31;17(8):1922-5. Epub 2015 Mar 31.

†Enamine, Ltd., Chervonotkatska 78, Kyiv 01103, Ukraine.

A set of novel SO2-containing azabicyclo[3.n.1]alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO2-containing building blocks for drug discovery.
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http://dx.doi.org/10.1021/acs.orglett.5b00608DOI Listing
April 2015

Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core.

Eur J Med Chem 2014 Sep 8;84:160-72. Epub 2014 Jul 8.

Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia; Department of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russia. Electronic address:

A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area.
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http://dx.doi.org/10.1016/j.ejmech.2014.07.023DOI Listing
September 2014

Insulin receptor-related receptor as an extracellular pH sensor involved in the regulation of acid-base balance.

Biochim Biophys Acta 2013 Oct 7;1834(10):2170-5. Epub 2012 Dec 7.

Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117437, Russia. Electronic address:

Recent studies of insulin receptor-related receptor (IRR) revealed its unusual property to activate upon extracellular application of mildly alkaline media, pH>7.9. The activation of IRR with hydroxyl anion has typical features of ligand-receptor interaction; it is specific, dose-dependent, involves the IRR extracellular domain and is accompanied by a major conformational change. IRR is a member of the insulin receptor minifamily and has been long viewed as an orphan receptor tyrosine kinase since no peptide or protein agonist of IRR was found. In the evolution, IRR is highly conserved since its divergence from the insulin and insulin-like growth factor receptors in amphibia. The latter two cannot be activated by alkali. Another major difference between them is that unlike ubiquitously expressed insulin and insulin-like growth factor receptors, IRR is found in specific sets of cells of only some tissues, most of them being exposed to extracorporeal liquids of extreme pH. In particular, largest concentrations of IRR are in beta-intercalated cells of the kidneys. The primary physiological function of these cells is to excrete excessive alkali as bicarbonate into urine. When IRR is removed genetically, animals loose the property to excrete bicarbonate upon experimentally induced alkalosis. In this review, we will discuss the available in vitro and in vivo data that support the hypothesis of IRR role as a physiological alkali sensor that regulates acid-base balance. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.
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http://dx.doi.org/10.1016/j.bbapap.2012.11.011DOI Listing
October 2013

Insulin receptor-related receptor as an extracellular alkali sensor.

Cell Metab 2011 Jun;13(6):679-89

Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.

The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.
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http://dx.doi.org/10.1016/j.cmet.2011.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119365PMC
June 2011

Molecular target characterization and antimyeloma activity of the novel, insulin-like growth factor 1 receptor inhibitor, GTx-134.

Clin Cancer Res 2011 Jul 1;17(14):4693-704. Epub 2011 Jun 1.

Department of Medical Oncology-Hematology, Princess Margaret Hospital, McLaughlin Centre for Molecular Medicine, Toronto, Ontario, Canada.

Purpose: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of cancers including multiple myeloma (MM). In this study, we describe GTx-134, a novel small-molecule inhibitor of IGF-1R and insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM.

Experimental Design: The activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma coculture experiments was assessed. Finally, the in vivo efficacy was evaluated in a human myeloma xenograft model.

Results: GTx-134 inhibited the growth of 10 of 14 myeloma cell lines (<5 μmol/L) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Coculture with insulin-growth factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134-induced cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134 enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells. Therapeutic efficacy of GTx-134 was shown against primary cells and xenograft tumors. Although dysregulation of glucose homeostasis was observed in GTx-134-treated mice, impairment of glucose tolerance was modest.

Conclusions: These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical application in combination with established antimyeloma treatments and novel targeted therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-3097DOI Listing
July 2011

Novel EphB4 monoclonal antibodies modulate angiogenesis and inhibit tumor growth.

Am J Pathol 2010 Apr 4;176(4):2029-38. Epub 2010 Feb 4.

Vasgene Thereapeutics Inc., Los Angeles, CA, USA.

EphB4 receptor tyrosine kinase and its cognate ligand EphrinB2 regulate induction and maturation of newly forming vessels. Inhibition of their interaction arrests angiogenesis, vessel maturation, and pericyte recruitment. In addition, EphB4 is expressed in the vast majority of epithelial cancers and provides a survival advantage to most. Here, we describe two anti-EphB4 monoclonal antibodies that inhibit tumor angiogenesis and tumor growth by two distinct pathways. MAb131 binds to fibronectin-like domain 1 and induces degradation of human EphB4, but not murine EphB4. MAb131 inhibits human endothelial tube formation in vitro and growth of human tumors expressing EphB4 in vivo. In contrast, MAb47 targets fibronectin-like domain 2 of both human and murine EphB4 and does not alter EphB4 receptor levels, but inhibits angiogenesis and growth of both EphB4-positive and EphB4-negative tumors in a mouse s.c. xenograft model. Combination of MAb47 and bevacizumab enhances the antitumor activity and induces tumor regression. Indeed, humanized antibodies hAb47 and hAb131 showed similar affinity for EphB4 and retained efficacy in the inhibition of primary tumor development and experimental metastasis.
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http://dx.doi.org/10.2353/ajpath.2010.090755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2843490PMC
April 2010