Abstract 5769: Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors

Abstract

Abstract We became interested in bicyclic tetrahydrothiazepine derivatives described in a Patent (WO 2016/139181) having immunomodulatory activities on CD3-activated T cells (CD4+ & CD8+) and NK cell increasing the secretion of several cytokines such as, e.g., IL-2, IFN-γ and/or TNF-α whereas corresponding unstimulated immune cells do not respond. Surprisingly - in contrast to what has been described in the patent - the N-H of the Amides 1 and 2 described in the patent was not required for potency and the oxadiazoles 1 and 2 were significantly more potent in T-cell proliferation and IL-2 release. Compound 1 was in vivo active in a single dose PD study in mice after CD3 activation and in a MC38 xenograft mice model showing single agent activity. Amide 1 and Amide 2 were identified in a phenotypic screen and the mode of action was unknown. Because of the promising pharmacological profile and in vivo activity, we were interested in the target. Here we describe how we identified the potential targets DGKα and DGKζ. Citation Format: Thomas Luebbers, Adrian Britschgi, Veronica Costa, Thomas Friess, Jean-Christophe Hau, Gordon Heidkamp, Holger Kuehne, Laetitia J. Martin, Filip Roudnicky, Manuel Tzouros, An Vandemeulebroucke. Target identification of T-cell activating immunomodulatory tetrahydrothiazepines: DGKα and DGKζ inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5769.