CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma - Article Abstract

Sep 24, 2026

Lymphoma is the most common hematologic malignancy, and improved immunochemotherapy still leaves a strong need for new targeted agents for both B- and T-cell cancers. This report characterizes cytidine triphosphate synthase 1 (CTPS1), a nonredundant rate-limiting enzyme in pyrimidine synthesis required for lymphoid proliferation. Small molecules selectively inhibit CTPS1 by binding to its ATP pocket, blocking in vitro proliferation, inducing apoptosis, and suppressing growth of neoplastic human B and T cells in vivo. A lead compound is in phase 1/2 for relapsed/refractory lymphoma (NCT05463263).

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Abstract

Background and unmet need

CTPS1 as a novel target

Small-molecule inhibition strategy

Preclinical efficacy and mechanism

Clinical development status

Article Open Access CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma Hélène Asnagli1 , Norbert Minet2 ,3 , Christina Pfeiffer4 , Eef Hoeben1 , Rebecca Lane5 , David Laughton5 , Louise Birch5 , Geraint Jones5 , Andrew Novak5 , Andrew E. Parker1 , Heinz Ludwig4 , Alain Fischer6 ,7 , Sylvain Latour2 ,3 , Philip A. Beer1 GRAPHICAL ABSTRACT Article Open Access CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma Hélène Asnagli1 , Norbert Minet2 ,3 , Christina Pfeiffer4 , Eef Hoeben1 , Rebecca Lane5 , David Laughton5 , Louise Birch5 , Geraint Jones5 , Andrew Novak5 , Andrew E. Parker1 , Heinz Ludwig4 , Alain Fischer6 ,7 , Sylvain Latour2 ,3 , Philip A. Beer1 Correspondence: Sylvain Latour ([sylvain.latour@inserm.fr](sylvain.latour@inserm.fr)); Philip A. Beer ([pb@step-ph.com](pb@step-ph.com)) . 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) . INTRODUCTION Cytotoxic chemotherapy has long been the mainstay of treatment for lymphoid cancers. Chemotherapy-induced inhibition of DNA synthesis has proven to be an effective means to kill tumor cells, as evidenced by the utility of drugs such as cytarabine and gemcitabine. More recently, advances in medicinal chemistry and understanding of cancer biology have started to move the field away from chemotherapy toward targeted agents, as exemplified by chronic lymphocytic leukemia where 1Step Pharma, Saint-Genis-Pouilly, France 2Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France 3Université de Paris, France 4Department of Medicine I, Klinik Ottakring, Wilhelminen Cancer Research Institute, Vienna, Austria 5Sygnature Discovery, Nottingham, United Kingdom 6INSERM UMR 1163, Imagine Institute, Paris, France 7Collège de France, Paris, France Supplemental digital content is available for this article. Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. HemaSphere (2023) 7:4(e864). [http://dx.doi.org/10.1097/HS9.0000000000000864](

FAQs

Why is CTPS1 considered a novel target in lymphoma?

CTPS1 plays an essential, nonredundant role in B-cell and T-cell proliferation through pyrimidine synthesis, and it is critical for lymphoid proliferation.

How do the developed small molecules inhibit CTPS1?

The inhibitor series binds to the CTPS1 adenosine triphosphate pocket, producing potent and highly selective CTPS1 inhibition.

What preclinical effects were observed after CTPS1 inhibition?

A potent CTPS1 inhibitor blocked in vitro proliferation of human neoplastic cells, induced apoptosis in most tested lymphoid cell lines, and inhibited growth of neoplastic B and T cells in vivo.

Sep 24, 2026

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