title: A pyrrolo-pyrimidine derivative targets human primary AML stem cells in vivo.
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.
authors.affiliation: Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yuki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Kuratani
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Takagi
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Junko
authors.initials: J
authors.lastname: Mikuni
authors.forename: Noriko
authors.initials: N
authors.lastname: Handa
authors.forename: Ikuko
authors.initials: I
authors.lastname: Ogahara
authors.forename: Akiko
authors.initials: A
authors.lastname: Sone
authors.forename: Yuho
authors.initials: Y
authors.lastname: Najima
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tomabechi
authors.forename: Motoaki
authors.initials: M
authors.lastname: Wakiyama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Uchida
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomizawa-Murasawa
authors.forename: Akiko
authors.initials: A
authors.lastname: Kaneko
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajita
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aoki
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Toshio
authors.initials: T
authors.lastname: Goto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051572:Proto-Oncogene Proteins c-hck / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D051572:Proto-Oncogene Proteins c-hck