@article{c61f20017bfe4e81ab39c8035851c1a0,
title = "Identification of a dual FLT3 and MNK2 inhibitor for acute myeloid leukemia treatment using a structure-based virtual screening approach",
abstract = "Fms-like tyrosine kinase 3 (FLT3) is considered a promising therapeutic target for acute myeloid leukemia (AML) in the clinical. However, monotherapy with FLT3 inhibitor is usually accompanied by drug resistance. Dual inhibitors might be therapeutically beneficial to patients with AML due to their ability to overcome drug resistance. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) phosphorylate eukaryotic translation initiation factor 4E (eIF4E), which brings together the RAS/RAF/ERK and PI3K/AKT/mTOR oncogenic pathways. Therefore, dual inhibition of FLT3 and MNK2 might have an additive effect against AML. Herein, a structure-based virtual screening approach was performed to identify dual inhibitors of FLT3 and MNK2 from the ChemDiv database. Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC50 values of 680 and 406 nM, respectively. In addition, the compound showed selectivity for both FLT3 and MNK2 in a panel of 82 kinases. The structure-activity relationship analysis and common interactions revealed interactions between K783-0308 analogs and FLT3 and MNK2. Furthermore, K783-0308 inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest. Taken together, the dual inhibitor K783-0308 showed promising results and can be potentially optimized as a lead compound for AML treatment.",
keywords = "Acute myeloid leukemia, Dual inhibitors, FLT3 inhibitors, MNK2 inhibitors, Structure-based virtual screening",
author = "Yen, {Shih Chung} and Chen, {Liang Chieh} and Huang, {Han Li} and HuangFu, {Wei Chun} and Chen, {Yi Ying} and {Eight Lin}, Tony and Lien, {Ssu Ting} and Tseng, {Hui Ju} and Sung, {Tzu Ying} and Hsieh, {Jui Hua} and Huang, {Wei Jan} and Pan, {Shiow Lin} and Hsu, {Kai Cheng}",
note = "Funding Information: This study was supported by the Ministry of Science and Technology ( MOST 108-2320-B-038-058-MY3 ). This research was also partially supported by Biomedical Translation Research Center, Academia Sinica (Grant No. AS-BRPT-110-06 ), Health and welfare surcharge of tobacco products (MOHW110-TDU-B-212-144020), “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, and the Warshel Institute for Computational Biology with funding from Shenzhen City and Longgang District in the People{\textquoteright}s Republic of China. Funding Information: This study was supported by the Ministry of Science and Technology (MOST 108-2320-B-038-058-MY3). This research was also partially supported by Biomedical Translation Research Center, Academia Sinica (Grant No. AS-BRPT-110-06), Health and welfare surcharge of tobacco products (MOHW110-TDU-B-212-144020), ?TMU Research Center of Cancer Translational Medicine? from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan, and the Warshel Institute for Computational Biology with funding from Shenzhen City and Longgang District in the People's Republic of China. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
doi = "10.1016/j.bioorg.2022.105675",
language = "English",
volume = "121",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Academic Press Inc.",
}