A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo

作者：Saito Yoriko; Yuki Hitomi; Kuratani Mitsuo; Hashizume Yoshinobu; Takagi Shinsuke; Honma Teruki; Tanaka Akiko; Shirouzu Mikako; Mikuni Junko; Handa Noriko; Ogahara Ikuko; Sone Akiko; Najima Yuho; Tomabechi Yuri; Wakiyama Motoaki; Uchida Naoyuki; Tomizawa Murasawa Mariko; Kaneko Akiko; Tanaka Satoshi; Suzuki Nahoko; Kajita Hiroshi; Aoki Yuki; Ohara Osamu; Shultz Leonard D; Fukami Takehiro; Goto Toshio; Taniguchi Shuichi; Yokoyama Shigeyuki; Ishikawa Fumihiko^*

来源：Science Translational Medicine, 2013, 5(181): 181ra52.

DOI：10.1126/scitranslmed.3004387

Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.

• 出版日期2013-4-17