Article
Health Care Sciences & Services
David J. Wooten, Melat Gebru, Hong-Gang Wang, Reka Albert
Summary: The study investigated the gene expression changes in FLT3-mutant AML cell lines in response to drug treatment, identifying seven gene programs involved in AML drug-induced changes. By constructing a network of FLT3-ITD AML and applying the BooleaBayes algorithm, a probabilistic, data-driven dynamical model of acquired resistance to drugs was created, revealing potential interventions to disrupt the drug response system and prevent resistance.
JOURNAL OF PERSONALIZED MEDICINE
(2021)
Article
Oncology
Xinhua Xiao, Peihong Wang, Weina Zhang, Jiayi Wang, Mansi Cai, Hua Jiang, Yingli Wu, Huizhuang Shan
Summary: Our study revealed that GNF-7 is a potent FLT3-ITD inhibitor, exhibiting strong anti-leukemia activity against primary FLT3-ITD AML samples. GNF-7 binds to FLT3 protein and inhibits downstream signaling pathways, including STAT5, PI3K/AKT, and MAPK/ERK. It also shows potent inhibitory activity against FLT3-ITD/F691L that confers resistance to quizartinib or gilteritinib. Additionally, GNF-7 exhibits cytotoxic effect on leukemic stem cells, significantly extends survival in a PDX model, and shows comparable therapeutic effects to gilteritinib.
CANCER CELL INTERNATIONAL
(2023)
Article
Multidisciplinary Sciences
Dinh Hoa Hoang, Dandan Zhao, Sergio Branciamore, Davide Maestrini, Ivan R. Rodriguez, Ya-Huei Kuo, Russell Rockne, Samer K. Khaled, Bin Zhang, Le Xuan Truong Nguyen, Guido Marcucci
Summary: In acute myeloid leukemia (AML), FLT3-ITD regulates the biogenesis of miR-126 and miR-155. FLT3-ITD induces the expression of miR-155, which down-regulates SHIP1 and increases AKT activity, leading to increased cell cycle progression. Additionally, miR-155 down-regulates SPRED1 and blocks the biogenesis of miR-126, resulting in decreased levels of mature miR-126.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Letter
Oncology
Peihong Wang, Xinhua Xiao, Yuyin Zhang, Baoyuan Zhang, Donghe Li, Mingzhu Liu, Xi Xie, Chenxuan Liu, Ping Liu, Ruibao Ren
Summary: Research has identified KX2-391 as a promising FLT3 inhibitor for treating AML patients, especially those with drug-resistant FLT3-ITD-TKD mutations, showing significant efficacy in inhibiting FLT3 phosphorylation and enhancing apoptosis in AML cell lines.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Hui Ma, Jiayan Cui, Zehui Liu, Wenqing Fang, Sisi Lu, Shuying Cao, Yuanyuan Zhang, Ji-An Chen, Lixue Lu, Qiong Xie, Yonghui Wang, Ying Huang, Kongfei Li, Hongyan Tong, Jin Huang, Weiqiang Lu
Summary: This study demonstrates that induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.
Article
Medicine, Research & Experimental
Dan Xu, Yishan Chen, Ying Yang, Zhao Yin, Changfen Huang, Qiang Wang, Ling Jiang, Xuejie Jiang, Changxin Yin, Qifa Liu, Guopan Yu
Summary: Autophagy plays a critical role in drug resistance in FLT3-ITD-positive AML. It can be activated by acquired mutation or bone marrow micro-environment (BME) and mediates resistance to FLT3 inhibitors. Inhibiting autophagy could be a promising strategy to overcome resistance.
JOURNAL OF TRANSLATIONAL MEDICINE
(2022)
Article
Oncology
Yi Liu, Jing Wei, Jiaxin Liu, Weina Ma, Yanting Duan, Daihong Liu
Summary: The study investigated the upregulation of AXL antigen expression in FLT3-ITD+ AML blast cells, as well as the cytotoxic effects of novel AXL-targeted agents on FLT3-mutant AML cell lines and blast cells. Combinations of AXL-targeted agents with AC220 showed synergistic cytotoxic effects and induced apoptosis in FLT3 inhibitor-resistant blast cells. The antileukemic effect of AXL-targeted agents may rely on their ability to block AXL, FLT3 and their downstream signaling pathways.
Article
Chemistry, Medicinal
Sheng Cao, Lan Ma, Yulin Liu, Mingming Wei, Yuhong Yao, Chen Li, Ruonan Wang, Ning Liu, Zhiqiang Dong, Xuechun Li, Ming Li, Xiaoji Wang, Cheng Yang, Guang Yang
Summary: In this study, dovitinib was chemically modified into CRBN-recruiting PROTACs, resulting in two active compounds with enhanced antiproliferative effects against FLT3-ITD+ AML cells and the ability to induce degradation of FLT3-ITD and KIT proteins while blocking their downstream signaling pathways. This study presents a promising strategy for developing novel therapies for FLT3-ITD+ AML.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Stefan Bjelosevic, Emily Gruber, Andrea Newbold, Carolyn Shembrey, Jennifer R. Devlin, Simon J. Hogg, Lev Kats, Izabela Todorovski, Zheng Fan, Thomas C. Abrehart, Giovanna Pomilio, Andrew Wei, Gareth P. Gregory, Stephin J. Vervoort, Kristin K. Brown, Ricky W. Johnstone
Summary: FLT3-ITD promotes serine synthesis in AML, making FLT3-ITD-driven leukemias dependent on serine for proliferation and survival. Pharmacologically exploiting this metabolic dependency can sensitize FLT3-ITD-driven AML to chemotherapy.
Review
Oncology
Shuai-Shuai Ge, Song-Bai Liu, Sheng-Li Xue
Summary: FLT3 mutations are common in AML and targeting FLT3 has significantly improved survival rates. However, resistance to FLT3 inhibitors is a pressing issue, and the development of novel treatments and multitarget strategies is needed.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Cell Biology
Sivasundaram Karnan, Ichiro Hanamura, Akinobu Ota, Souichi Takasugi, Ayano Nakamura, Miyuki Takahashi, Kaori Uchino, Satsuki Murakami, Md Wahiduzzaman, Lam Quang Vu, Md Lutfur Rahman, Muhammad Nazmul Hasan, Toshinori Hyodo, Hiroyuki Konishi, Shinobu Tsuzuki, Kazuhiro Yoshikawa, Susumu Suzuki, Ryuzo Ueda, Masayuki Ejiri, Yoshitaka Hosokawa, Akiyoshi Takami
Summary: STAT5 activation in genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulates CD52 expression, while the anti-CD52 antibody alemtuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) and shows antitumor effects in FLT3(ITD/WT) cells.
CELL DEATH DISCOVERY
(2021)
Article
Pharmacology & Pharmacy
Fangfang Wang, Jingcao Huang, Tingting Guo, Yuhuan Zheng, Li Zhang, Dan Zhang, Fujue Wang, Duolan Naren, Yushan Cui, Xiaoyan Liu, Ying Qu, Hongmei Luo, Yan Yang, Haichen Wei, Yong Guo
Summary: The combination treatment of HHT with quizartinib has shown synergistic effects on inhibiting cell growth, inducing apoptosis, and prolonging survival in mice with FLT3-ITD AML, suggesting it as a promising therapeutic strategy.
BIOCHEMICAL PHARMACOLOGY
(2021)
Editorial Material
Hematology
Sara E. Meyer
Summary: In this issue of Blood, Li et al.1 explore the role of FLT3 internal tandem duplication (ITD) in orchestrating transcriptional and epigenetic programs in myeloid progenitor cells, resulting in distinct functional outputs.
Review
Oncology
Tobias R. Haage, Burkhart Schraven, Dimitrios Mougiakakos, Thomas Fischer
Summary: Mutations of the FLT3 gene are common in AML, occurring as internal tandem duplications (FLT3-ITD) in approximately 30% of cases. The specific insertion sites of FLT3-ITD show significant heterogeneity in biological and clinical features. Non-juxtamembrane domain (non-JMD) FLT3-ITD insertions have been associated with worse clinical outcomes and resistance to treatment. This review highlights the importance of considering non-JMD FLT3-ITD mutations in risk stratification and developing targeted therapies for AML.
Article
Chemistry, Medicinal
Caroline W. Karanja, Kofi S. Yeboah, Herman O. Sintim
Summary: Immune cells respond to bacterial and host-derived molecules to produce an immune response, while some pathogens can weaken host response through specific enzymes. Researchers have identified compounds that inhibit MTB CDN PDE, but there remains a lack of such specific inhibitors.
ACS INFECTIOUS DISEASES
(2021)
Article
Microbiology
Kenneth Onyedibe, Samira Elmanfi, Uma K. Aryal, Eija Kononen, Ulvi Kahraman Gursoy, Herman O. Sintim
Summary: This study reveals that cyclic dinucleotides (CDNs) derived from bacteria not only regulate cytokine production via STING, but also broadly affect many critical processes in human cells, including interferon signaling pathways and other not fully characterized pathways. This highlights the importance of understanding the response of human gingival fibroblasts to bacterial-derived CDNs.
JOURNAL OF ORAL MICROBIOLOGY
(2022)
Article
Chemistry, Medicinal
George A. Naclerio, Kenneth Onyedibe, Caroline W. Karanja, Uma K. Aryal, Herman O. Sintim
Summary: Drug-resistant bacterial pathogens continue to cause high mortality rates, necessitating new chemical modalities for treatment. Halogenated N-(1,3,4-oxadiazol-2-yl)benzamides are an interesting class of antimicrobial agents with multiple modes of action and low propensity for MRSA resistance development.
ACS INFECTIOUS DISEASES
(2022)
Article
Chemistry, Medicinal
Neetu Dayal, Kenneth I. Onyedibe, Whitney M. Gribble, Herman O. Sintim
Summary: According to the National Institute of Health (NIH), the majority of human microbial infections are caused by bacterial biofilms and are resistant to FDA approved drugs. Therefore, there is a need for the development of antibiotics that can target biofilms. Researchers have synthesized pentafluorosulfanyl (SF5)-containing compounds and expanded the compounds in the library to discover potential therapeutics. The results showed that these compounds can effectively kill bacteria in biofilms without toxic effects on human cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Clement Opoku-Temeng, Brett Freedman, Adeline R. Porter, Scott D. Kobayashi, Liang Chen, Barry N. Kreiswirth, Frank R. DeLeo
Summary: Carbapenem-resistant Klebsiella pneumoniae isolates, specifically multilocus sequence type 258 (ST258), have developed resistance to multiple classes of antibiotics and can cause severe infections in susceptible individuals. This study investigates the impact of subinhibitory concentrations of antibiotics on the capsule production and survival of K. pneumoniae in normal human serum (NHS). Surprisingly, certain antibiotics, such as mupirocin, enhanced the survival of ST258 isolates in NHS and also increased the production of capsular polysaccharide (CPS). Further analyses revealed that mupirocin treatment and/or culture in NHS upregulated genes related to the stringent response and serum resistance in ST258 isolates. These findings suggest that the response of K. pneumoniae to mupirocin and human serum contributes to decreased serum susceptibility through a multifactorial process, and further investigation is needed to understand the impact on clinical outcomes in the human host.
MICROBIOLOGY SPECTRUM
(2022)
Article
Chemistry, Medicinal
Kenneth I. Onyedibe, Ansley M. Nemeth, Neetu Dayal, Richard D. Smith, Jones Lamptey, Robert K. Ernst, Roberta J. Melander, Christian Melander, Herman O. Sintim
Summary: Researchers have discovered a compound called HSD1624 that enhances the effectiveness of the antibiotic colistin against resistant bacteria in multiple strains.
ACS INFECTIOUS DISEASES
(2023)
Editorial Material
Chemistry, Multidisciplinary
Christopher Vennard, Herman O. Sintim
ACS CENTRAL SCIENCE
(2022)
Article
Oncology
Ujjwol Khatri, Neetu Dayal, Xueqing Hu, Elizabeth Larocque, Nimishetti Naganna, Tao Shen, Xuan Liu, Frederick W. Holtsberg, M. Javad Aman, Herman O. Sintim, Jie Wu
Summary: Selpercatinib and pralsetinib are approved RET kinase inhibitors for treating RET-altered cancers, but resistance mutations have been identified. This study investigates the sensitivities of different G810 mutants to these inhibitors and identifies new compounds for inhibiting resistant mutations.
MOLECULAR CANCER THERAPEUTICS
(2023)
Editorial Material
Chemistry, Medicinal
Christopher Vennard, Temitope Oropo, Herman O. Sintim
Summary: Vancomycin-like drugs target peptidoglycan by binding to the C-terminal d-Ala-d-Ala dipeptide. An engineered vancomycin with enhanced affinity for the peptidoglycan stem peptide, possibly through interactions with meso-diaminopimelic acid, displays increased killing of mycobacteria.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Allison L. Kempen, Nickolas R. Brauer, Herman O. Sintim
Summary: The study describes the synthesis of a newly discovered 3H-pyrazolo[4,3-f]quinoline core through a multi-component Doebner-Povarov reaction, which has the ability to selectively inhibit cancer-associated kinases FLT3 and haspin. The researchers report the discovery of a potent dual FLT3/haspin inhibitor, HSK205, which shows remarkable activity against FLT3-driven AML cell lines.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Wilson W. S. Ong, Neetu Dayal, Riddhi Chaudhuri, Jones Lamptey, Herman O. O. Sintim
Summary: The cGAS-STING axis is important in protecting higher organisms against pathogens or cancer. However, overactivation of this pathway can lead to inflammation, which is harmful to the host. STING antagonists, such as HSD1077, have been discovered and shown to inhibit STING binding, suppressing interferon expression and potentially managing various inflammatory diseases.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Desmond Akwata, Allison L. Kempen, Jones Lamptey, Neetu Dayal, Nickolas R. Brauer, Herman O. Sintim
Summary: Current treatment options for multiple myeloma patients are limited, and there is a need for effective targeted therapies. Recent studies have shown that the transforming growth factor-beta activated kinase (TAK1) is overexpressed in multiple myeloma, providing hope for the discovery of TAK1 inhibitors.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Desmond Akwata, Allison L. Kempen, Neetu Dayal, Nickolas R. Brauer, Herman O. Sintim
Summary: FLT3 is expressed in immune and cancer cells and has potential applications in the treatment of acute myeloid leukemia and chronic pain. However, current FLT3 inhibitors also inhibit other important kinases, which limits their use in non-oncology applications.
