P1248: CTP SYNTHASE 1 IS A NOVEL TARGET IN T CELL CANCERS, WITH SMALL MOLECULE INHIBITION INDUCING DEATH OF NEOPLASTIC HUMAN T CELLS IN VITRO AND INHIBITION OF THEIR GROWTH IN AN IN VIVO XENOTRANSPLANT MODEL

• DOI: 10.1097/01.hs9.0000847856.37391.3c
• Publication Date: 2022-06-23T14:19:59Z
• Authors: P. Beer; H. Asnagli; N. Minet; E. Hoeben; A. Parker; A. Fischer; S. Latour
• Keywords: Jurkat cells; Viability assay; Matrigel; Growth inhibition

Background: T cell lymphomas are rare haematological cancers characterised by poor response to cytotoxic chemotherapy with resulting unmet clinical need. Recent studies have identified targeted therapies as a promising approach improve outcomes. CTPS1, which catalyses the rate limiting step in pyrimidine synthesis, plays an essential and non-redundant role B proliferation but is complemented homologous CTPS2 isoform outside of haemopoietic system [1]. [1] E. Martin et al., Nature. 2014 Jun 12; 510(7504):288-292. Aims: To assess impact selective CTPS1 inhibition on survival human neoplastic cells. Methods: Recombinant enzymatic activity was assessed quantitating cytidine triphosphate RapidFire Mass Spectrometry. HEK cells lacking either or were generated using CRISPR technology; viability measured after 3-5 days incubation test compounds CellTiter-Glo 2.0. For cellular complementation assay, Jurkat transduced lentivirus carrying different constructs cloned into pLVX-EF1α-IRES-mCherry backbone; cultured without compound 72 hours later CellTiter-Blue. vitro cancer line studies, incubated for compound; CellTiterGlo death CellTiterTox Green. vivo experiments, sub-lethally irradiated female NOD-SCID mice transplanted subcutaneously 107 embedded Matrigel. Mice randomised n=8 per treatment group when tumours reached mean 150 mm3. Test vehicle control administered every two days. Tumour volume twice weekly. Results: STP938 potent reversible low molecular weight inhibitor shows >1,300-fold selectivity over CTPS2. Selectively confirmed CTPS2, consequently dependent respectively, (Figure A). A assay ATP pocket binding site series highlighted residues critical exhibited anti-proliferative against broad range tested vitro; malignancies significantly more sensitive than solid lines, being most B). Exposure (Jurkat MOLT-4) resulted concentration induction C). In model neoplasia, where immunodeficient mice, showed dose tumour growth D). Image:Summary/Conclusion: STP938, novel small molecule favourable pharmaceutical properties, inhibits vivo. represents target cancers. currently prepared first study patients relapsed refractory lymphoma.