A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo
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DOI：
10.1126/scitranslmed.3004387
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发表时间：
2013-04-17
影响因子：
17.1
通讯作者：
Ishikawa, Fumihiko
中科院分区：
文献类型：
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作者：
Saito, Yoriko;Yuki, Hitomi;Ishikawa, Fumihiko
在常规化疗中存活的白血病干细胞（LSC）被认为有助于疾病复发，导致急性髓性白血病（AML）患者的长期预后不良。我们以前确定了Src家族激酶（SFK）成员，造血细胞激酶（HCK），作为一种分子靶点，与人类正常造血干细胞（HSC）相比，在人类原代LSC中高度差异表达。我们进行了一个大规模的化学库筛选，整合了高通量酶抑制试验，在电脑结合预测，晶体结构测定，并发现了一个候选人HCK抑制剂，RK-20449，吡咯并嘧啶衍生物与酶的IC 50（半最大抑制浓度）在亚纳摩尔范围内。晶体结构显示RK-20449结合HCK的活化口袋。RK-20449对移植有高度侵袭性治疗耐药性AML的非肥胖糖尿病（NOD）/重度联合免疫缺陷（SCID）/IL 2 rg（null）小鼠的体内给药显著降低了人LSC和非干细胞AML负荷。通过消除耐化疗的LSC，RK-20449可能有助于预防复发并改善AML患者的预后。
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.