A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition.

中文翻译：

---

的发现ñ - （6-氟-1-氧代-1,2-二氢异喹啉-7-基）-5 - [（3 - [R）-3-羟基吡咯烷-1-基]噻吩-2-磺酰胺（LSN 3213128），一种有效且选择性的非经典抗叶酸氨基咪唑-4-羧酰胺核糖核苷酸甲酰基转移酶（AICARFT）抑制剂，可有效抑制癌症异种移植模型中的肿瘤

癌症的标志是不受限制的增殖，这可能导致对DNA和RNA生物合成所需的嘌呤和嘧啶碱基从头合成的需求增加。这些合成途径在癌症中经常被上调，并涉及各种叶酸依赖性酶。抗叶酸药已作为临床上使用的溶瘤剂得到了证明。我们最近的研究工作已经产生了LSN 3213128（化合物28a），这是一种新颖的，选择性的，非经典的，口服可生物利用的抗叶酸药物，对嘌呤生物合成途径中的一种酶氨基咪唑-4-羧酰胺核糖核苷酸甲酰基转移酶（AICARFT）具有有效的抑制作用。用化合物28a抑制AICARFT结果导致NCI-H460和MDA-MB-231met2癌细胞系中5-氨基咪唑4-羧酰胺核糖核苷酸（ZMP）急剧升高并抑制了生长。在基于小鼠的三阴性乳腺癌（TNBC）的异种移植模型中使用这种抑制剂进行治疗会导致肿瘤生长受到抑制。