GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Abstract 519: EVOEXS21546 is a novel non-brain penetrant A2AR inhibitor for cancer immunotherapy with accelerated drug development
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 519-519
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 519-519
    Abstract: Evotec and Exscientia are collaborating to develop an innovative drug discovery platform for accelerating small molecule development in Immuno-Oncology. The primary focus is to target the immunosuppressive adenosine pathway. We have firstly sought to generate a novel and selective, non-brain penetrant A2AR antagonist. EVOEX21546 has been selected as our lead candidate with in vitro potency on primary human CD3+ T-lymphocytes for inducing the recovery of IL-2 production after CADO-mediated inhibition of T-cell activation. In addition, we have demonstrated the compound’s effect on other key biological features of T-cell activation including IFN-gamma production and T-cell proliferation. ADME/DMPK data show that EVOEX21546 has a favourable pharmacological profile consistent with its evaluation in syngeneic tumour models. Furthermore, we are pursuing efforts to understand the Mechanism-of-Action of EVOEXS21546 in order to identify the most relevant biomarker of activity for clinical translation. Finally, from the perspective to accelerate the IND submission, EVOEXS21546 entered an INDiGO campaign, an integrated and rapid process to reach IND complemented by high-end integrated CMC. These results, generated in the frame of the A2AR inhibitor pathway, have paved the way to an optimized process for identifying, improving and accelerating the path from drug discovery to the entering into the clinic for Immuno-Oncology drugs. Citation Format: Pierre Fons, Andy Bell, Michael Esquerre, Stephanie Versluys, Florie Bertrand, Iva Hopkins-Navratilova, Sean Robinson, Virgile Visentin, Adrian Schreyer, Richard Cox, Emilie Mirey, Emilie Pelissier, Celia bergeaud, Simone Culurgioni, Jeremy Besnard, Andrew Payne, Jerome Menegotto, Frederic Machet, Celine Poussereau-Pomie, Eric Cogo, Michael Paillasse, Federica Ferigo, Sabrina Pagliarusco, Joanna Lisztwan, Mark Whittaker, Craig Johnstone, Andrew Hopkins. EVOEXS21546 is a novel non-brain penetrant A2AR inhibitor for cancer immunotherapy with accelerated drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; C ancer Res 2019;79(13 Suppl):Abstract nr 519.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-519
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 1731: EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1731-1731
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1731-1731
    Abstract: Elevated levels of adenosine found in the tumor microenvironment have been highlighted as a potential mechanism contributing to the restricted efficacy of immune checkpoint inhibitors. While the advent of these inhibitors has brought significant benefit to patients with cancer, there is still significant unmet need even in disease indications for which these agents are approved. Adenosine has an immune-suppressive effect in tumors, and pre-clinical and early clinical evidence indicates that antagonists of the GPCR family of adenosine receptors are able to relieve that suppression and restore anti-tumor immune cell activity. EXS21546 is a non-furan, selective antagonist of the A2A receptor with low brain penetration. Using EXS21546, we show that activity at the A2A receptor is sufficient for complete restoration of T-cell function in the presence of high concentrations of adenosine analogue. Translational studies with EXS21546 have been undertaken using patient samples to better understand its activity in signaling and disease-relevant endpoints. We will present data characterizing the activity of EXS21546 ex vivo in patient-derived whole blood samples. Interrogation of primary cancer cells from pancreatic and lung cancer patients treated with EXS21546 ex vivo by phenotypic image-based screening, demonstrated that EXS21546 reduces the relative fraction of viable cancer cells while inducing an expansion of the viable CD8+ T cell fraction in the presence of high concentrations of an adenosine analogue. Together, these data indicate the potential for EXS21546 may have a role in cancer therapy. EXS21546 has completed pre-IND studies in preparation for initiation of first-in-human clinical studies. Citation Format: Andrew Payne, Pierre Fons, Isabella Alt, Joost van Ham, Christina Taubert, Andy Bell, Stephanie Versluys, Florie Bertrand, Virgile Visentin, Emilie Mirey, Emilie Pelissier, Michael Paillasse, Sabrina Pagliarusco, Gregory Vladimer, Mark Whittaker. EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1731.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1731
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Abstract 507: Identification of CD73 and A2AR/CD73 small molecule inhibitors for cancer immunotherapy as single agents or in combination with Immune-checkpoint therapies
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 507-507
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 507-507
    Abstract: Adenosine generated by CD73 is a key driver of immunosuppression in the hypoxic tumour microenvironment (TME) and particularly involved in angiogenic process and immunity. In immune-inflamed tumours, with CD8+ T-cell infiltrates, adenosine signalling is a cause of resistance to immune checkpoint therapies (ICTs) through the inhibition of T-cells, NK cells and more largely of the overall antitumor immunity. Evotec and Exscientia are collaborating to develop an innovative drug discovery platform for accelerating small molecule development in Immuno-Oncology targeting the adenosine pathway. The platform has integrated a unique biophysical screening approach for the adenosine receptors and CD73 to drive automated medicinal chemistry design with a translational-focused screening cascade. We have initiated research of CD73 specific inhibitory molecules based on SPR fragment screening and have identified lead compounds which fully bind in the active site of the CD73 protein in both the open and closed states. In vitro functional potency has been demonstrated for the CD73 inhibitors for inhibiting adenosine production by Rapid Fire technology performed using CD73 recombinant protein. Moreover, we demonstrated that CD73 inhibitors induce recovery of AMP-induced inhibition of T-cells activation as measured through IL-2 production. The series are under lead optimization to improve ADME/DMPK parameters in order to enable evaluation in PK/PD assays and in vivo efficacy studies specifically developed for the project. Finally, from the perspective of developing a dual pharmacological profile for A2AR and CD73 inhibition, we have assessed, using primary human CD3+ T-lymphocytes isolated from healthy donors, the synergy between the inhibition of the two targets in order to enhance the recovery of T-cell activation. We have demonstrated that EVOEXS21546, our pre-development A2AR inhibitor candidate, and our lead compound for CD73 inhibition act in synergy in functional human T-cell assays. Our SPR screening approach has also identified hit compounds with dual bispecific pharmacological activity against both A2AR and CD73. Citation Format: Pierre Fons, Andrew Bell, Michael Esquerre, Stephanie Versluys, Florie Bertrand, Adrian Schreyer, Iva Hopkins-Navratilova, Leonardo-Silvestre Hernani, Celia Bergeaud, Celine Poussereau-Pomie, Ghislaine Marchand, Sean Robinson, Simone Culurgioni, Richard Cox, Jeremy Besnard, Andrew Payne, Peter Ray, Emilie Pelissier, Michael Paillasse, Joanna Lisztwan, Craig Johnstone, Mark Whittaker, Andrew Hopkins. Identification of CD73 and A2AR/CD73 small molecule inhibitors for cancer immunotherapy as single agents or in combination with Immune-checkpoint therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 507.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-507
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Stratocumulus adjustments to aerosol perturbations disentangled with a causal approach
    Springer Science and Business Media LLC ; 2023
    In:  npj Climate and Atmospheric Science Vol. 6, No. 1 ( 2023-08-29)
    Details
    In: npj Climate and Atmospheric Science, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2023-08-29)
    Abstract: A large fraction of the uncertainty around future global warming is due to the cooling effect of aerosol-liquid cloud interactions, and in particular to the elusive sign of liquid water path (LWP) adjustments to aerosol perturbations. To quantify this adjustment, we propose a causal approach that combines physical knowledge in the form of a causal graph with geostationary satellite observations of stratocumulus clouds. This allows us to remove confounding influences from large-scale meteorology and to disentangle counteracting physical processes (cloud-top entrainment enhancement and precipitation suppression due to aerosol perturbations) on different timescales. This results in weak LWP adjustments that are time-dependent (first positive then negative) and meteorological regime-dependent. More importantly, the causal approach reveals that failing to account for covariations of cloud droplet sizes and cloud depth, which are, respectively, a mediator and a confounder of entrainment and precipitation influences, leads to an overly negative aerosol-induced LWP response. This would result in an underestimation of the cooling influence of aerosol-cloud interactions.
    Type of Medium: Online Resource
    ISSN: 2397-3722
    URL: Article
    DOI: 10.1038/s41612-023-00452-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2925628-8
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    TRY plant trait database – enhanced coverage and open access
    Wiley ; 2020
    In:  Global Change Biology Vol. 26, No. 1 ( 2020-01), p. 119-188
    Details
    In: Global Change Biology, Wiley, Vol. 26, No. 1 ( 2020-01), p. 119-188
    Abstract: Plant traits—the morphological, anatomical, physiological, biochemical and phenological characteristics of plants—determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits—almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
    Type of Medium: Online Resource
    ISSN: 1354-1013 , 1365-2486
    URL: Issue
    URL: Article
    DOI: 10.1111/gcb.v26.1
    DOI: 10.1111/gcb.14904
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2020313-5
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Hybrid forward osmosis-reverse osmosis for wastewater reuse and seawater desalination: Understanding the optimal feed solution to minimise fouling
    Elsevier BV ; 2018
    In:  Process Safety and Environmental Protection Vol. 117 ( 2018-07), p. 523-532
    Details
    In: Process Safety and Environmental Protection, Elsevier BV, Vol. 117 ( 2018-07), p. 523-532
    Type of Medium: Online Resource
    ISSN: 0957-5820
    URL: Article
    DOI: 10.1016/j.psep.2018.05.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 2008004-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...