淋巴瘤是最常见的血液恶性肿瘤之一，并且在全球十大流行癌症中。尽管现代免疫化学治疗方案已经改善了患者的生存率，但治疗B细胞和T细胞恶性疾病仍需要新型的靶向药物。胞嘧啶合成的速率限制步骤催化剂CTPS1在B细胞和T细胞增殖中发挥着至关重要的作用，但红细胞系外类似物CTPS2可作为CTPS1的替代品。该研究描述了CTPS1作为B细胞和T细胞癌症的新靶点的发现和特征化。已开发出一系列小分子，显示对CTPS1具有强效和高度选择性的抑制作用。位点定向突变研究确定，CTPS1的三磷酸腺苷作用口袋是这种小分子系列的结合位点。在临床前研究中，CTPS1的强效和高度选择性小分子抑制剂阻断了人类肿瘤细胞的体外增殖，对淋巴肿瘤的效力最强。重要的是，药理学上的CTPS1抑制引起了大多数淋巴细胞系的凋亡，从而证明了其细胞毒性作用机制。选择性CTPS1抑制还能在体内抑制人类B细胞和T细胞的增长。这些研究结果将CTPS1确定为淋巴恶性肿瘤的新疗法靶点。该系列化合物中的一种正在进行1/2临床研究，用于治疗复发/难治性B细胞和T细胞淋巴瘤（NCT05463263）。版权所有©2023作者。由沃尔特斯·克鲁弗健康公司代表欧洲血液学协会出版。

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).Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.