Targeting Lymphomas and Leukemias: The Therapeutic Potential of STP938, a Selective CTPS1 Inhibitor

The study explores the significance of cellular metabolism reprogramming in cancer, particularly focusing on the pyrimidine synthesis pathway, which is crucial for tumor growth and survival. Inhibitors targeting enzymes in this pathway have been tested clinically but with limited success due to toxicity issues. The research highlights the role of CTP synthase 1 (CTPS1) in lymphocyte proliferation and its potential as a target for cancer treatment. A rare mutation affecting CTPS1 activity has been linked to impaired lymphocyte proliferation, suggesting that inhibiting CTPS1 could be a strategy to combat hematological malignancies without affecting other cell types.

The research introduces STP938, a selective CTPS1 inhibitor, and tests its anti-tumor effects on a panel of 200 cancer cell lines. The study uses a 2D monolayer assay to measure cell viability and assesses the impact of STP938 on intracellular nucleotide levels in activated T-cells. Apoptosis is evaluated in Jurkat T-ALL cells and WI38 fibroblasts, and murine xenograft studies are conducted to evaluate the anti-tumor effects of CTPS1 inhibitors.

Results show that STP938 effectively inhibits the proliferation of hematological cancer cells, with 77% of these cell lines being highly sensitive to the inhibitor. The T-cell derived cell lines are particularly responsive, with many showing an IC50 of less than 10nM. STP938 selectively depletes CTP without affecting ATP or GTP levels, and induces apoptosis in Jurkat T-ALL cells in a dose-dependent manner. The WI38 fibroblasts remain unaffected. In murine xenograft models, oral administration of the CTPS1 inhibitor demonstrates a dose-dependent reduction in tumor growth.

The conclusion emphasizes that inhibiting CTPS1 can selectively disrupt pyrimidine nucleotide synthesis in hematological malignancies, inducing apoptosis in lymphocyte cells without impacting other cell types that utilize CTPS2. The orally bioavailable STP938 shows promise as a targeted therapeutic for treating hematological cancers.