3VS5

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

Saito, Y., Yuki, H., Kuratani, M., Hashizume, Y., Takagi, S., Honma, T., Tanaka, A., Shirouzu, M., Mikuni, J., Handa, N., Ogahara, I., Sone, A., Najima, Y., Tomabechi, Y., Wakiyama, M., Uchida, N., Tomizawa-Murasawa, M., Kaneko, A., Tanaka, S., Suzuki, N., Kajita, H., Aoki, Y., Ohara, O., Shultz, L.D., Fukami, T., Goto, T., Taniguchi, S., Yokoyama, S., Ishikawa, F.

(2013) Sci Transl Med 5: 181ra52-181ra52

• PubMed: 23596204 Search on PubMed
• DOI: https://doi.org/10.1126/scitranslmed.3004387
• Primary Citation of Related Structures:  
  3VRY, 3VRZ, 3VS0, 3VS1, 3VS2, 3VS3, 3VS4, 3VS5, 3VS6, 3VS7


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.