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

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Adult, Aged, Animals, Antineoplastic Agents, Bone Marrow Transplantation, Crystallography, X-Ray, Drug Resistance, Neoplasm, Female, Hematopoiesis, Humans, Leukemia, Myeloid, Acute, Male, Mice, Middle Aged, Neoplastic Stem Cells, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-hck, Pyrimidines, Pyrroles, RNA, Small Interfering, Small Molecule Libraries, Tumor Cells, Cultured, Young Adult

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Sci Transl Med 2013 Apr 17; 5(176):176ra32




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. Sci Transl Med 2013 Apr 17; 5(176):176ra32