Cho, Hanna Shin, Injae Ju, Eunhye Choi, Seunghye Hur, Wooyoung Kim, Haelee Hong, Eunmi Kim, Nam Doo Choi, Hwan Geun Gray, Nathanael S. Sim, Taebo 2024-01-19T21:34:43Z 2024-01-19T21:34:43Z 2021-09-05 2018-09-27 0022-2623 https://pubs.kist.re.kr/handle/201004/120888 GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound lli is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML. English AMER CHEMICAL SOC ACUTE MYELOGENOUS LEUKEMIA HUMAN CANCER CRYSTAL-STRUCTURES TYROSINE KINASE MEK INHIBITORS TARGETING RAS BCR-ABL DISCOVERY PERSPECTIVES ACTIVATION First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia Article 10.1021/acs.jmedchem.8b00882 1 JOURNAL OF MEDICINAL CHEMISTRY, v.61, no.18, pp.8353 - 8373 JOURNAL OF MEDICINAL CHEMISTRY 61 18 8353 8373 scie scopus 000446142000019 2-s2.0-85053693105 Chemistry, Medicinal Pharmacology & Pharmacy Article ACUTE MYELOGENOUS LEUKEMIA HUMAN CANCER CRYSTAL-STRUCTURES TYROSINE KINASE MEK INHIBITORS TARGETING RAS BCR-ABL DISCOVERY PERSPECTIVES ACTIVATION AML