Journal Article

CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients

Smith, G, Lasho, T, Fantino, E, Pardanani, A, Tefferi, A, Burns, C J

2009

Overview

Somatic mutations in Janus kinase 2 (JAK2), including JAK2 V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC 50 =11 and 18 n M , respectively), with significantly less activity against other kinases, including JAK3 (IC 50 =155 n M ). CYT387 inhibits growth of Ba/F3- JAK2 V617F and human erythroleukemia (HEL) cells (IC 50 ∼1500 n M ) or Ba/F3- MPL W515L cells (IC 50 =200 n M ), but has considerably less activity against BCR–ABL harboring K562 cells (IC=58 000 n M ). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3- TEL-JAK2 ) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3- TEL-JAK3 ), and STAT-5 phosphorylation was inhibited in HEL cells with an IC 50 =400 n M . Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Alleles / Animals / BCR-ABL protein / Biological and medical sciences / Blood cancer / Cancer Research / Cell Line, Tumor - drug effects / Cell Line, Tumor - enzymology / Cell lines / Cells, Cultured - drug effects / Cells, Cultured - enzymology / Colony-Forming Units Assay / Critical Care Medicine / Diseases of red blood cells / Drug Evaluation, Preclinical / Erythroleukemia / Erythropoietin / Erythropoietin - pharmacology / Hematologic and hematopoietic diseases / Hematology / Humans / Inhibitory Concentration 50 / Intensive / Internal Medicine / Janus kinase / Janus Kinase 1 - antagonists & inhibitors / Janus kinase 2 / Janus Kinase 2 - antagonists & inhibitors / Janus Kinase 2 - genetics / Kinases / Leukemia, Erythroblastic, Acute - pathology / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Medical sciences / Medicine / Medicine & Public Health / Mice / Mutation / Neoplasia / Oncogene Proteins, Fusion - antagonists & inhibitors / Oncology / original-article / Pathogenesis / Patients / Phenotype / Phosphorylation / Phosphotransferases / Physiological aspects / Polycythemia / Polycythemia vera / Polycythemia Vera - enzymology / Polycythemia Vera - genetics / Polycythemia Vera - pathology / Polycythemias / Protein Kinase Inhibitors - pharmacology / Protein-Tyrosine Kinases - antagonists & inhibitors / Receptors, Thrombopoietin - genetics / Selectivity / STAT Transcription Factors - metabolism / Stat5 protein / Substrate Specificity / Transcription