ABSTRACT
To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.
Subject(s)
Antineoplastic Agents/pharmacology , Electron Transport Complex I/antagonists & inhibitors , Leukemia, Myeloid, Acute/metabolism , Oxazoles/pharmacology , Oxidative Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Triazoles/pharmacology , Animals , Biomarkers , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Hematopoiesis/drug effects , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Mice , Models, Biological , Receptor, ErbB-2/antagonists & inhibitorsABSTRACT
The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.
Subject(s)
Fetal Blood/drug effects , Hematopoiesis/drug effects , Hematopoietic Stem Cells/drug effects , Indoles/pharmacology , Pyrimidines/pharmacology , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Regeneration/drug effects , Animals , Cell Culture Techniques , Fetal Blood/cytology , Fetal Blood/physiology , Genetic Therapy/methods , Hematopoiesis/physiology , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/physiology , Humans , Immunocompromised Host , Indoles/chemistry , Mice , Pyrimidines/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacologyABSTRACT
Cortisol and the glucocorticoid receptor (GR) signaling pathway has been linked to the development of diabetes and metabolic syndrome. In vivo, 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) catalyzes the conversion of inactive cortisone to its active form, cortisol. Existing clinical data have supported 11ß-HSD1 as a valid therapeutic target for type 2 diabetes. In our research program, (R)-1,1,1-trifluoro-2-(3-((R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)phenyl)propan-2-ol (HSD-016) was discovered to be a potent, selective, and efficacious 11ß-HSD1 inhibitor and advanced as a clinical candidate. Herein, a reliable and scalable synthesis of HSD-016 is described. Key transformations include an asymmetric synthesis of a chiral tertiary alcohol via Sharpless dihydroxylation, epoxide formation, and subsequent mild reduction. This route ensured multikilogram quantities of HSD-016 necessary for clinical studies.
