| 1. |
- Pippione, Agnese C., et al.
(author)
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4-Hydroxy-N -[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide: A novel inhibitor of the canonical NF-κB cascade
- 2017
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In: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 8:9, s. 1850-1855
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Journal article (peer-reviewed)abstract
- The NF-κB signaling pathway is a validated oncological target. Here, we applied scaffold hopping to IMD-0354, a presumed IKKβ inhibitor, and identified 4-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-1,2,5-thiadiazole-3-carboxamide (4) as a nM-inhibitor of the NF-κB pathway. However, both 4 and IMD-0354, being potent inhibitors of the canonical NF-κB pathway, were found to be inactive in human IKKβ enzyme assays.
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| 2. |
- Sainas, Stefano, et al.
(author)
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Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds
- 2017
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 129, s. 287-302
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Journal article (peer-reviewed)abstract
- A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC5016 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.
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| 3. |
- Sainas, Stefano, et al.
(author)
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Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Aryloxyaryl Moiety
- 2022
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:19, s. 12701-12724
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Journal article (peer-reviewed)abstract
- In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC50 1.2 nM), we kept improving the structure-activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4 (IC50 7.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC50 74 nM), superior to those of brequinar (EC50 249 nM) and boosted when in combination with dipyridamole. Finally, compound 4 has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.
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| 4. |
- Sainas, Stefano, et al.
(author)
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Targeting Acute Myelogenous Leukemia Using Potent Human Dihydroorotate Dehydrogenase Inhibitors Based on the 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold : SAR of the Biphenyl Moiety
- 2021
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:9, s. 5404-5428
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Journal article (peer-reviewed)abstract
- The connection with acute myelogenous leukemia (AML) of dihydroorotate dehydrogenase (hDHODH), a key enzyme in pyrimidine biosynthesis, has attracted significant interest from pharma as a possible AML therapeutic target. We recently discovered compound 1, a potent hDHODH inhibitor (IC50 = 1.2 nM), able to induce myeloid differentiation in AML cell lines (THP1) in the low nM range (EC50 = 32.8 nM) superior to brequinar's phase I/II clinical trial (EC50 = 265 nM). Herein, we investigate the 1 drug-like properties observing good metabolic stability and no toxic profile when administered at doses of 10 and 25 mg/kg every 3 days for 5 weeks (Balb/c mice). Moreover, in order to identify a backup compound, we investigate the SAR of this class of compounds. Inside the series, 17 is characterized by higher potency in inducing myeloid differentiation (EC50 = 17.3 nM), strong proapoptotic properties (EC50 = 20.2 nM), and low cytotoxicity toward non-AML cells (EC30(Jurkat) > 100 μM).
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| 5. |
- Sainas, Stefano, et al.
(author)
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Targeting myeloid differentiation using potent 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based human dihydroorotate dehydrogenase (hDHODH) inhibitors.
- 2018
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In: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 61:14, s. 6034-6055
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Journal article (peer-reviewed)abstract
- Human dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5-a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This paper reports the design, synthesis, SAR, X-ray crystallography, biological assays and physicochemical characterization of the new class of hDHODH inhibitors.
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| 6. |
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| 7. |
- Dozza, Marco, 1978, et al.
(author)
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Do cyclists on e-bikes behave differently than cyclists on traditional bicycles?
- 2014
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In: Proceedings of the 3rd International Cycling Safety Conference, Nov 18-19, Göteborg, Sweden.
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Conference paper (peer-reviewed)abstract
- Cycling is a healthy, environmentally-friendly and enjoyable activity, which unfortunately also claims more than 2000 lives every year in Europe. Many municipalities across Europe are wag-ing successful campaigns to increase cycling and, as a consequence, reduce pollution and con-gestion. However, at least in the short term, a surge in cycling will also challenge existing infrastructure, regulations, and the interaction among different road users. Further, cycling nature is changing as new electrified bicycles (e-bikes), able to maintain a constant 25km/h speed independent of road gradient or wind, become more and more prevalent. The extent to which e-bikes and their increasing prevalence impact safety is currently unknown and very hard to simulate with statistical models. In 2012, the BikeSAFE project collected 1474 km of naturalistic cycling data from traditional bi-cycles. In 2013, the e-BikeSAFE project collected 1549 km of naturalistic data from e-bikes. All studies took place in Göteborg in the same period of the year, and as much as possible in-volved the same participants. While these naturalistic data sets are limited and possibly not representative of the cycling situation in all of Europe, they are also the most advanced data today available for comparing how traditional and electrical bicycles behave in traffic, thus of-fering a promising test bed for developing data analysis methodologies.Five random video clips were extracted for each participant from the data collected in BikeSAFE and e-BikeSAFE, forming an overall analysis database of 140, 30-s long, full HD, video clips. Video reduction identified which road users were involved in the interactions with the traditional and electric bikes. During the analysis, potential influencing factors (e.g. bicycle lane width, gradient, and curvature) were also taken into account. Information from reduction of e-bike and traditional-bike videos was compared by means of odds ratios and combined with subjective data from questionnaires to determine the extent to which safety concerns about e-bike are legitimate.Results show that e-bikes and traditional bicycles are ridden differently: cyclists riding e-bikes experience more intense and different interactions with other road users, and prefer different riding conditions, possibly because of their higher speed. Further, specific infrastructures (as crossings) and secondary tasks (as using a phone) may be particularly dangerous for e-bikers. The results presented in this paper provide new ideas for the design of safer bicycle lanes and more conspicuous e-bikes.
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| 8. |
- Dozza, Marco, 1978, et al.
(author)
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How do drivers overtake cyclists?
- 2016
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In: Accident Analysis and Prevention. - : Elsevier BV. - 0001-4575. ; 88, s. 29-36
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Journal article (peer-reviewed)abstract
- In Europe, the number of road crashes is steadily decreasing every year. However, the incidence of bicycle crashes is not declining as fast as that of car crashes. In Sweden, cyclists are the most frequently injured road users. Collisions between bicycles and motorized vehicles are of particular concern because the high speed and large mass of motorized vehicles creates a high risk of serious injury to cyclists. In Sweden’s urban areas, bicycle lanes keep bicycles separated from motorized vehicles, but on rural roads bicycle lanes are often absent, requiring drivers to interact with cyclists— usually by overtaking them. During this maneuver, the driver regulates speed and lateral position, negotiating with potential oncoming traffic to stay within their comfort zone while approaching and passing the cyclist.In this study an instrumented bicycle recorded 145 overtaking maneuvers performed by car and truck drivers on public rural roads in Sweden. The bicycle was equipped with a LIDAR and two cameras to assess how drivers approached and circumvented the bicycle. The collected data allowed us to identify four overtaking phases and quantify the corresponding driver comfort zones. The presence of an oncoming vehicle was the factor that most influenced the maneuver, whereas neither vehicle speed, lane width, shoulder width nor posted speed limit significantly affected the driver comfort zone or the overtaking dynamics.
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| 9. |
- Dozza, Marco, 1978, et al.
(author)
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Using naturalistic data to assess e-cyclist behavior
- 2016
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In: Transportation Research Part F: Traffic Psychology and Behaviour. - : Elsevier BV. - 1369-8478. ; 41, s. 217-226
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Journal article (peer-reviewed)abstract
- In Europe, the use of electric bicycles is rapidly increasing. This trend raises important safety concerns: Is their use compatible with existing infrastructure and regulations? Do they present novel safety issues? How do they impact other traffic? Monitoring e-cyclist behavior in real traffic would allow us to begin addressing these concerns. This study instrumented electric bicycles to monitor e-cyclists’ behavior in a naturalistic fashion. Data was collected from 12 bicyclists, each of whom rode an instrumented bicycle for two weeks. In total, 1500 km worth of data were collected, including 88 critical events (crashes and near-crashes). Analysis of these critical events identified pedestrians, light vehicles and other bicycles as main threats to a safe ride. Other factors also contributed to crash causation, such as being in proximity to a crossing or encountering a vehicle parked in the bicycle lane. A comparison between electric and traditional bicycles was enabled by the availability of data from a previous study a year earlier, which collected naturalistic cycling data from traditional bicycles using the same instrumentation as in this study. Electric bicycles were found to be ridden faster, on average, than traditional bicycles, in addition to interacting differently with other road users. The results presented in this study also suggest that countermeasures to bicycle crashes should be different for electric and traditional bicycles. Finally, increasing electric bicycle conspicuity appears to be the easiest, most obvious way to increase their safety.
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| 10. |
- Farah, Haneen, et al.
(author)
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Drivers’ Decision Making of Overtaking Strategies of Cyclists on Rural Roads–A Driving Simulator Experiment
- 2019
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Conference paper (other academic/artistic)abstract
- Cyclists’ involvement in road crashes has not been improving with the same magnitude as other modes of transport. Especially, the interactions between cyclists and motorized traffic can end up with the most severe types of crashes. To improve the safety of these interactions, a thorough understanding of road users’ decisions and behaviours is first needed. In this study, the authors focus on drivers’ overtaking manoeuvres of cyclists on rural roads. The main objective of this study is to develop a model that can predict drivers’ decisions whether to perform a flying or an accelerative overtaking manoeuvre when approaching a cyclist in the presence of oncoming traffic. A driving simulator study was designed to collect trajectory data of the overtaking vehicle, cyclist, and oncoming traffic. Drivers’ characteristics data was collected using surveys. In total, 37 drivers participated, each of them performing 7 overtaking manoeuvres. Out of 259 overtaking manoeuvres, 168 were flying and 91 were accelerative. Two binary logistic regression models were developed and estimated. In the two models, the time-to-collision and the driver’s speed significantly affect the decision on the overtaking manoeuvre type. In the first model, the correlations among the observations of the same driver were captured through the drivers’ characteristics. In the second model, these correlations were captured through a driver specific error term. The overall performance is 87.7% and 94.9% for the first and second models, respectively. In the paper the authors discuss the usability of each model for policy making, system design, and system evaluation.
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