CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma

Abstract

Lymphoma is the most common hematological malignancy and is among the 10 most prevalent cancers worldwide. Although survival has been improved by modern immunochemotherapeutic regimens, there remains a significant need for novel targeted agents to treat both B-cell and T-cell malignancies. Cytidine triphosphate synthase 1 (CTPS1), which catalyzes the rate-limiting step in pyrimidine synthesis, plays an essential and nonredundant role in B-cell and T-cell proliferation but is complemented by the homologous CTPS2 isoform outside the hemopoietic system. This report describes the identification and characterization of CTPS1 as a novel target in B- and T-cell cancers. A series of small molecules have been developed which show potent and highly selective inhibition of CTPS1. Site-directed mutagenesis studies identified the adenosine triphosphate pocket of CTPS1 as the binding site for this small molecule series. In preclinical studies, a potent and highly selective small molecule inhibitor of CTPS1 blocked the in vitro proliferation of human neoplastic cells, showing the highest potency against lymphoid neoplasms. Importantly, pharmacological CTPS1 inhibition induced cell death by apoptosis in the majority of lymphoid cell lines tested, thus demonstrating a cytotoxic mechanism of action. Selective CTPS1 inhibition also inhibited the growth of neoplastic human B- and T- cells in vivo. These findings identify CTPS1 as a novel therapeutic target in lymphoid malignancy. A compound from this series is in phase 1/2 clinical studies for the treatment of relapsed/refractory B- and T-cell lymphoma (NCT05463263).

CTPS1 inhibition synergizes with replication stress signaling inhibition inMYC-amplified Group 3 medulloblastoma

“…In this study, using functional genomics and small molecule inhibition, we characterize CTPS1 as a targetable vulnerability in G3 MB and identify MYC-amplified MB as exquisitely dependent on de novo pyrimidine but not purine synthesis. Unlike in hematological malignancies where CTPS1 inhibition alone significantly inhibits growth and increases apoptosis 13,16 , we observe limited cytotoxicity as a single agent in G3 MB.…”

“…CTP synthase 1 (CTPS1), the rate limiting enzyme in the de novo synthesis of the nucleotide CTP, is one such metabolic target 11,12 . CTPS1 has previously been shown as a vulnerability in various adult solid and hematologic tumors [13][14][15][16] and a small molecule inhibitor of CTPS1 is currently in clinical trials (NCT05463263). Further, a recent paper linked MYC expression to CTPS1 inhibitor sensitivity, demonstrating synthetic lethality in colorectal cancer 17 .…”

Connecting Hippo pathway and cytoophidia inDrosophilaposterior follicle cells

“…The length of cytoophidia is related with the 14 / 42 concentration of CTPS in the cell [63]. In mice, inhibiting CTPS1 suppresses tumor growth and induces apoptosis [64], indicating that CTPS plays a role in tumor metabolism.…”

“…However, CTPS cytoophidia inhibit enzymatic activity in S. cerevisiae, E. coli and D. melanogaster [9,48,67,68]. CTPS is considered a potential drug target [64]. The glutamine analog 6-Diazo-5-oxo-L-norleucine (DON) binds to the glutamine binding site in the CTPS GAT domain, inhibiting CTPS activity and increasing cytoophidia length [17,69].…”

Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice

“…Organ transplantation might also represent a good indication for CTPS1 targeting. A selective inhibitor of CTPS1 is currently being evaluated in relapsed and refractory T and B cell lymphoma patients (NCT05463263) 13 , 14 .…”