公开(公告)号：US06593306B1

公开(公告)日：2003-07-15

申请号：US09467932

申请日：1999-12-21

申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

IPC分类号： A61K3170

CPC分类号： A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/708 ,  C07H19/14

摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2′-deoxyquanosine-5′-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deaza-nucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。

公开(公告)号：US6004939A

公开(公告)日：1999-12-21

申请号：US879457

申请日：1997-06-20

申请人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

发明人： Shih-Fong Chen ,  Ira Maine ,  Sean M. Kerwin ,  Terace M. Fletcher ,  Miquel Salazar ,  Blain Mamiya ,  Makoto Wajima ,  Bradford E. Windle

IPC分类号： A61K31/70 ,  C07H19/14

CPC分类号： A61K31/7064 ,  A61K31/7068 ,  A61K31/7072 ,  A61K31/7076 ,  A61K31/708 ,  C07H19/14

摘要： It was found that normal human stem cells produce a regulated non-processive telomerase activity, while cancer cells produce a processive telomerase activity. Nucleotide analogs, such as 7-deaza-2'-deoxyquanosine-5'-triphosphate (7-deaza-dGTP) were found to be substrates for processive telomerase and incorporated into telomeric sequence. The incorporation of this nucleotide subsequently affected the processivity of telomerase, converting processive telomerase to non-processive telomerase. The incorporation of this nucleotide analogs was also found to inhibit formation of G-quartets by telomeric sequence. Other methods for converting cancer processive telomerase to the more benign non-processive telomerase include partially cleaving the telomerase RNA. The nucleoside analogs were found to be capable of a variety of activities including mediating allosteric-like inhibition of telomerase, premature termination and shortening of telomeric DNA, destabilization of telomeric structure and function and eventually cell death. Understanding the mechanisms of telomerase modulation by the 7-deazanucleotides has allowed the design of new telomerase inhibitors, modulators and agents for affecting telomere structure and function. These discoveries have application in the treatment of cancer.

摘要翻译： 发现正常的人类干细胞产生调节的非进程性端粒酶活性，而癌细胞产生进行性的端粒酶活性。 发现核苷酸类似物，如7-脱氮-2'-脱氧鸟苷-5'-三磷酸（7-脱氮-dGTP）是进行性端粒酶的底物并掺入端粒序列。 该核苷酸的并入随后影响端粒酶的进程，将进程性端粒酶转化为非进程性端粒酶。 还发现该核苷酸类似物的掺入通过端粒序列抑制G四重奏的形成。 将癌症进程性端粒酶转化为更良性非进程性端粒酶的其他方法包括部分切割端粒酶RNA。 发现核苷类似物具有多种活性，包括介导端粒酶的变构类似的抑制，早期终止和端粒DNA的缩短，端粒结构和功能的不稳定以及最终的细胞死亡。 了解7-脱氮核苷酸端粒酶调节的机制使得设计了新的端粒酶抑制剂，调节剂和药剂来影响端粒结构和功能。 这些发现可用于治疗癌症。