A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo

  • Sci Transl Med. 2013 Apr 17;5(181):181ra52. doi: 10.1126/scitranslmed.3004387.
Yoriko Saito  1 ,  Hitomi Yuki ,  Mitsuo Kuratani ,  Yoshinobu Hashizume ,  Shinsuke Takagi ,  Teruki Honma ,  Akiko Tanaka ,  Mikako Shirouzu ,  Junko Mikuni ,  Noriko Handa ,  Ikuko Ogahara ,  Akiko Sone ,  Yuho Najima ,  Yuri Tomabechi ,  Motoaki Wakiyama ,  Naoyuki Uchida ,  Mariko Tomizawa-Murasawa ,  Akiko Kaneko ,  Satoshi Tanaka ,  Nahoko Suzuki ,  Hiroshi Kajita ,  Yuki Aoki ,  Osamu Ohara ,  Leonard D Shultz ,  Takehiro Fukami ,  Toshio Goto ,  Shuichi Taniguchi ,  Shigeyuki Yokoyama ,  Fumihiko Ishikawa
Affiliations
  • 1. Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
PMID: 23596204 DOI: 10.1126/scitranslmed.3004387
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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