Nonami, Atsushi Sattler, Martin Weisberg, Ellen Liu, Qingsong Zhang, Jianming Patricelli, Matthew P. Christie, Amanda L. Saur, Amy M. Kohl, Nancy E. Kung, Andrew L. Yoon, Hojong Sim, Taebo Gray, Nathanael S. Griffin, James D. 2024-01-20T07:02:51Z 2024-01-20T07:02:51Z 2021-09-05 2015-05-14 0006-4971 https://pubs.kist.re.kr/handle/201004/125446 Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules (eg, RAF kinase) have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in preclinical models of acute myelogenous leukemia and acute lymphoblastic leukemia. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of mitogen-activated protein kinase kinase kinase kinase 2 (germinal center kinase). Similar to genetic synthetic lethal approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes. English AMER SOC HEMATOLOGY GERMINAL CENTER KINASE CANCER-CELLS INHIBITOR ACTIVATION PATHWAY RAS POLYPHARMACOLOGY RESISTANCE DISCOVERY SURVIVAL Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach Article 10.1182/blood-2014-12-615906 1 BLOOD, v.125, no.20, pp.3133 - 3143 BLOOD 125 20 3133 3143 scie scopus 000355689000018 2-s2.0-84946770965 Hematology Hematology Article GERMINAL CENTER KINASE CANCER-CELLS INHIBITOR ACTIVATION PATHWAY RAS POLYPHARMACOLOGY RESISTANCE DISCOVERY SURVIVAL NRAS