Article
Oncology
Javier Bregante, Anna Schoenbichler, Daniel Poeloeske, Lina Degenfeld-Schonburg, Garazi Monzo Contreras, Emir Hadzijusufovic, Elvin D. de Araujo, Peter Valent, Richard Moriggl, Anna Orlova
Summary: FLT3-ITD mutations are common and detrimental in AML, with AML cells quickly developing resistance to FLT3 kinase inhibitors. Through a drug screen, new potential therapeutics like ispinesib, WS6, ponatinib, and cabozantinib have been identified for FLT3-ITD+ AML. Combination therapy with cabozantinib and ispinesib shows strong efficacy against FLT3-ITD+ AML, suggesting promising novel treatment options for this clinical challenge.
Article
Medical Laboratory Technology
L. E. Y. I. N. G. CHEN, Z. H. A. O. Y. U. WU, L. I. N. A. N. YANG, Y. U. Y. U. N. CHEN, W. E. N. H. O. N. G. WANG, L. I. T. I. N. G. CHENG, C. H. O. N. G. L, D. A. Z. H. A. O. L, L. I. A. N. G. Y. O. N. G. XIA, J. I. A. CHEN, L. I. N. A. TANG, L. I. ZHANG, S. H. I. Y. I. ZHANG, J. I. E. LUO
Summary: Hand-foot skin reaction (HFSR) is a common and debilitating side effect caused by multikinase inhibitors (MKIs). This study proposes a potential treatment using glyceryl trinitrate (GTN) to reverse MKI-induced toxicity and alleviate HFSR symptoms. The mechanism of action involves upregulation of VEGF/VEGFR downstream signaling pathways.
TRANSLATIONAL RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Summary: FLT3 mutations are the most common genetic alterations in AML and have a negative impact on clinical prognosis. The development of FLT3 inhibitors has shown promise in improving outcomes for AML patients with FLT3 mutations. Midostaurin and gilteritinib have recently been approved as frontline treatments for AML by the FDA. Clinical trials are ongoing to explore the use of FLT3 inhibitors in different treatment settings. The accumulation of data on FLT3 inhibitors will be important evidence for guiding the use of these inhibitors in AML patients with FLT3 mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Vanessa Marensi, Karen R. Keeshan, David J. MacEwan
Summary: AML is an aggressive blood cancer with a high mortality rate, especially for patients with FLT3 gene mutations, leading to difficulties in developing personalized therapeutic strategies due to mutation-driven drug resistance. Targeting FLT3 receptor tyrosine kinase has become a treatment strategy, but limited clinical impact has been observed with current tyrosine kinase inhibitors against FLT3-ITD.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Joshua J. Lara, Alfonso E. Bencomo-Alvarez, Mayra A. Gonzalez, Idaly M. Olivas, James E. Young, Jose L. Lopez, Vanessa V. Velazquez, Steven Glovier, Mehrshad Keivan, Andres J. Rubio, Sara K. K. Dang, Jonathan P. Solecki, Jesse C. Allen, Desiree N. Tapia, Boranai Tychhon, Gonzalo E. Astudillo, Connor Jordan, Darshan S. Chandrashekar, Anna M. Eiring
Summary: PSMD1 and PSMD3 were identified as prognostic biomarkers and potential therapeutic targets in chronic myeloid leukemia and multiple solid tumors. In this study, the expression of 19S proteasome subunits in acute myeloid leukemia patients with FLT3 gene mutations was analyzed. The results showed that high levels of PSMD3 expression were associated with worse overall survival. PSMD3 knockdown impaired colony formation of FLT3+ AML cell lines and increased overall survival in xenograft models. Proteomics analyses suggested a role for PSMD3 in neutrophil degranulation and energy metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Fansheng Ran, Yun Liu, Jian Zhu, Xuexian Deng, Hongmei Wu, Weizhi Tao, Xudong Xie, Yirong Hu, Yanan Zhang, Yong Ling
Summary: A novel class of aminopyrimidine-based dual-target inhibitors, designed for the treatment acute myeloid leukemia, effectively inhibited the activities of BTK, FLT3, and FLT3(D835Y) mutant. These compounds showed potent antiproliferative activities against leukemia cells and induced autophagy and apoptosis. In vivo studies demonstrated that compound 14m significantly suppressed the growth of MV-4-11 cells without apparent toxicity. These dual-target inhibitors hold promise for further optimization and mechanism studies.
BIOORGANIC CHEMISTRY
(2023)
Article
Oncology
Pierre-Yves Dumas, Arnaud Villacreces, Amelie V. Guitart, Ali El-habhab, Layal Massara, Olivier Mansier, Audrey Bidet, Delphine Martineau, Solene Fernandez, Thibaut Leguay, Arnaud Pigneux, Isabelle Vigon, Jean-Max Pasquet, Vanessa Desplat
Summary: The study revealed that gilteritinib exhibited a stronger proapoptotic effect on FLT3-ITD AML cells in a simulated bone marrow microenvironment compared to quizartinib, and was more effective at targeting leukemia cells. Additionally, gilteritinib showed a toxicity profile on normal murine hematopoiesis similar to quizartinib.
CLINICAL CANCER RESEARCH
(2021)
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
Biochemistry & Molecular Biology
Eman M. E. Dokla, Amal Kamal Abdel-Aziz, Sandra N. Milik, Martin J. McPhillie, Saverio Minucci, Khaled A. M. Abouzid
Summary: In this study, a benzimidazole-based small molecule, 4ACP, was developed with nanomolar activity against FLT3 and TrKA, two key enzymes associated with AML. 4ACP demonstrated selective antiproliferative activity and downregulated signaling pathways in AML cells, leading to cell death and cell cycle arrest.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Hematology
Nianci Chen, Jiajia Pan, Yile Zhou, Liping Mao, Yinjun Lou, Jiejing Qian, Gaixiang Xu, Juying Wei, De Zhou, Lihong Shou, Li Huang, Minchao Yan, Hui Zeng, Cuihua Fan, Gongqiang Wu, Weiying Feng, Hongyan Tong, Jie Jin, Huafeng Wang
Summary: This retrospective analysis investigated the efficacy and safety of different gilteritinib-based combination therapies in relapsed/refractory FLT3-mutated AML patients. The study found that gilteritinib plus hypomethylating agent and venetoclax combination therapy showed higher response rates and may serve as an effective bridge to transplantation.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
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
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)
Review
Biochemistry & Molecular Biology
Baku Acharya, Debasmita Saha, Daniel Armstrong, Naga Rajiv Lakkaniga, Brendan Frett
Summary: FLT3 mutations are commonly found in AML and are associated with poor prognosis. Despite the development of FLT3 inhibitors, the five-year overall survival rate for newly diagnosed AML remains low. Midostaurin was the first FDA-approved FLT3 inhibitor in the US and Europe. This review summarizes the clinical success stories and other pre-clinical and clinical investigations of FLT3 inhibitors.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Bongki Ko, Yongsoo Jang, Min Ha Kim, Thai Thi Lam, Hye Kyung Seo, Pyeonghwa Jeong, Munkyung Choi, Keon Wook Kang, So-Deok Lee, Jin-Hee Park, Myungjin Kim, Sun-Young Han, Yong-Chul Kim
Summary: This study developed novel inhibitors targeting mutant FLT3 kinases through chemical moieties optimization. The optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, as well as strong antiproliferative activity against AML cell line MV4-11 cells. It also showed single-digit nanomolar inhibitory values in mutant FLT kinase expressed cell lines.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Oncology
Yuta Kaito, Mitsuhito Hirano, Muneyoshi Futami, Masanori Nojima, Hideto Tamura, Arinobu Tojo, Yoichi Imai
Summary: Acute myeloid leukemia (AML) relapse is associated with escape from anti-tumor immunity. Changes in CD155 and CD112 expression affect tumor immunity and FLT3 inhibitors could be a potential solution for AML immunotherapy.
Article
Biochemistry & Molecular Biology
Krupal P. Jethava, Priya Prakash, Palak Manchanda, Harshit Arora, Gaurav Chopra
Summary: Targeting live cell organelles is crucial for imaging, understanding, and controlling specific biochemical processes. In this study, a modular one-step synthetic strategy was developed to create new fluorescent probes targeting lysosomal, mitochondrial, and nucleus in live cells. The differentiation in cellular localization and pH activation abilities of the probes were achieved by specific functional group changes in the central scaffold.
Article
Biochemistry & Molecular Biology
Caroline W. Karanja, Nimishetti Naganna, Nader S. Abutaleb, Neetu Dayal, Kenneth Onyedibe, Uma Aryal, Mohamed N. Seleem, Herman O. Sintim
Summary: This study presents a new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, which exhibit strong bactericidal activity against a range of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus strains. Representative compounds in this class, HSN584 and HSN739, are capable of reducing methicillin-resistant S. aureus load in macrophages and show a low propensity for developing resistance. Comparative global proteomics and macromolecule biosynthesis assays suggest that HSN584 perturbs S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety holds promise as a new scaffold for the development of potent antibacterial agents against multidrug-resistant Gram-positive bacteria.
Article
Chemistry, Medicinal
Jian Huang, Qiong Shi, Namrta Choudhry, Hongmei Li, Chenglu Yang, Julia Kalashova, Ziqi Yan, Jinhua Li, Mallu Chenna Reddy, Sridhar Goud Gopala, Shenqiu Zhang, Jing Zhang, Naganna Nimishetti, Dun Yang
Summary: Mechanism-informed phenotypic screening was used to identify and optimize compounds that mimic the genetic depletion of AURKB kinase. These compounds exhibited potent cytotoxic activities in various cancer cell lines and showed excellent drug-like properties. The findings suggest that seven-membered lactam-based analogs could be valuable for the development of new antimitotic agents for cancer treatment.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemical Research Methods
Caitlin E. Randolph, Connor H. Beveridge, Sanjay Iyer, Stephen J. Blanksby, Scott A. McLuckey, Gaurav Chopra
Summary: Despite the challenges in analyzing the extensive structural diversity of lipids, a new charge-switching mass spectrometric approach combined with liquid chromatography has been developed to differentiate isomeric lipids. This technique successfully identifies the position of anteiso-methyl branch points in fatty acids, without the need for reference standards. This method holds promise for the structural identification of branched-chain fatty acids.
JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
(2022)
Article
Chemistry, Medicinal
Gang Lv, Qiong Shi, Ting Zhang, Jinhua Li, Julia Kalashova, Yan Long, Yin Sun, Chao Li, Namrta Choudhry, Hongmei Li, Chenglu Yang, Xiaohu Zhou, Mallu Chenna Reddy, Kishore Kumar Anantoju, Rajesh Jupelli, Shenqiu Zhang, Jing Zhang, Thaddeus Allen, Hong Liu, Naganna Nimishetti, Dun Yang
Summary: Activity-based drug screens have led to the development of inhibitors for aurora kinases (AURKs), but disrupting the localization of AURKB is an alternative approach worth exploring. The pan-AURK inhibitor AMG900 was shown to disrupt the localization of AURKB rather than inhibiting its phosphorylation of H3 at Ser10. Further studies revealed that certain derivatives of 2-phenoxy-3,4'-bipyridine have the potential to be developed as effective therapeutics for malignancy by delocalizing AURKB.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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)
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)
Article
Chemistry, Multidisciplinary
Jonathan Fine, Prageeth R. Wijewardhane, Sheik Dawood Beer Mohideen, Katelyn Smith, Jameson R. Bothe, Yogita Krishnamachari, Alexandra Andrews, Yong Liu, Gaurav Chopra
Summary: This study introduces a machine learning-based model for predicting the chemical stability of drug products using formulation conditions and aggregation curves. The results demonstrate that the machine learning models can accurately predict degradation and potency of drug products. Additionally, there is a relationship between physical stability and chemical stability.
PHARMACEUTICAL RESEARCH
(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.
Review
Chemistry, Analytical
Caitlin E. Randolph, Palak Manchanda, Harshit Arora, Sanjay Iyer, Pooja Saklani, Connor Beveridge, Gaurav Chopra
Summary: Lipidomics, as a standalone subdiscipline of metabolomics, has received considerable attention in the past decade. Mass spectrometry has emerged as the preferred tool for lipid identification and detection due to its sensitivity and versatility. However, traditional lipidomics methods based on bulk cell samples do not capture the cellular heterogeneity present in seemingly homogeneous cell populations. This review focuses on recent advances in mass spectrometry-based single cell lipidomics and explores the reasons behind the slow development of single-cell lipidomics techniques.
TRAC-TRENDS IN ANALYTICAL CHEMISTRY
(2023)
