b-43 and Leukemia--Myeloid--Acute

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.

Topics: 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