Cytidine 5'-triphosphate synthetase 1 (CTPS1)

Cytidine 5'-triphosphate synthetase 1 (CTPS1) is a rate-limiting enzyme in the de novo pyrimidine synthesis pathway, responsible for the ATP-dependent conversion of uridine triphosphate (UTP) to cytidine triphosphate (CTP) [1.1.1, 1.1.2]. While its paralog CTPS2 provides CTP for most tissues, CTPS1 is uniquely essential for the rapid proliferation of activated T and B lymphocytes during an immune response [1.2.1, 1.2.2]. This specific requirement makes CTPS1 an attractive therapeutic target for treating hematological malignancies, such as lymphomas and leukemias, as well as autoimmune disorders, by selectively inhibiting the expansion of pathological immune cells while sparing other tissues [1.3.1, 1.3.2]. Recent research also highlights its role in solid tumors, where many cancer cells exhibit a dependency on CTPS1 for DNA synthesis, and in viral infections like SARS-CoV-2, where the virus exploits the enzyme to drive its own replication [1.2.3, 1.3.2]. Selective small-molecule inhibitors, such as dencatistat (STP938), are currently in clinical development to exploit these vulnerabilities, offering a precision oncology approach with a potentially improved safety profile compared to non-selective nucleotide synthesis inhibitors [1.3.2, 1.5.2]. Furthermore, CTPS1 has been identified as a prognostic biomarker in several cancers, including mantle cell lymphoma and colorectal cancer, where high expression correlates with poor patient outcomes [1.4.1, 1.4.2].

Other names

CTP synthase 1CTP synthetase 1UTP--ammonia ligase 1GATD5IMD24PYRG1

Selective inhibition of CTP synthase 1 activity, which blocks the conversion of UTP to CTP, leading to depletion of the intracellular CTP pool and subsequent inhibition of DNA and RNA synthesis and cell proliferation [1.1.2, 1.3.2].