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    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
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  • 2
    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
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