Article
Oncology
Yun Xu, Ziting Wang, Lei Zhang, Congying Gao, Fahui Li, Xueming Li, Yu Ke, Hong-Min Liu, Zhenbo Hu, Liuya Wei, Zhe-Sheng Chen
Summary: The compound JOA can inhibit the proliferation of chronic myeloid leukemia cells, including those with the BCR-ABL-T315I mutation, and induce cell differentiation. This effect may be mediated by the inhibition of the BCR-ABL/c-MYC signaling pathway. JOA shows potential as a lead compound for overcoming imatinib resistance in CML therapy.
Article
Oncology
Karoline Gleixner, Yuksel Filik, Daniela Berger, Christina Schewzik, Gabriele Stefanzl, Irina Sadovnik, Lina Degenfeld-Schonburg, Gregor Eisenwort, Mathias Schneeweiss-Gleixner, Konstantin Byrgazov, Wolfgang R. Sperr, Jiri Mayer, Thomas Lion, Peter Valent
Summary: Research shows that the combination of asciminib and ponatinib has a synergistic effect on inducing apoptosis in CML cells, especially effective against cells with T315I+ BCR-ABL1 compound mutations, with further enhanced anti-leukemic effects when used in combination with HU.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Tingting Lu, Jiangyan Cao, Fengming Zou, Xixiang Li, Aoli Wang, Wenliang Wang, Huamin Liang, Qingwang Liu, Chen Hu, Cheng Chen, Zhenquan Hu, Wenchao Wang, Lili Li, Jian Ge, Yang Shen, Tao Ren, Jing Liu, Ruixiang Xia, Qingsong Liu
Summary: CHMFL-48 is a novel type II kinase inhibitor that potently inhibits the wild-type BCR-ABL kinase and a panel of imatinib-resistant mutants. This drug shows strong inhibitory activity in a cellular context, blocking autophosphorylation of BCR-ABL kinase, affecting downstream signaling mediators, and inducing cell cycle progression blockade and apoptosis.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Elena V. Koroleva, Yuri V. Kornoushenko, Anna D. Karpenko, Ivan P. Bosko, Julia V. Siniutsich, Zhanna V. Ignatovich, Alexander M. Andrianov
Summary: An integrated computational approach was used to identify potential inhibitors of Bcr-Abl tyrosine kinase, an enzyme involved in chronic myeloid leukemia. Five compounds were found to effectively block the enzyme activity and exhibit high binding affinity comparable to FDA-approved kinase inhibitors. These compounds may serve as good scaffolds for the design of novel anticancer agents.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Oncology
Angela McLigeyo, Jamilla Rajab, Peter Oyiro, Mohammed Ezzi, Yatich Bett, Matilda Ong'ondi, Andrew Odhiambo, Sitna Mwanzi, Nicholas Othieno-Abinya
Summary: This study analyzed the baseline characteristics and factors associated with cytopenia in Chronic Myeloid Leukemia patients treated with imatinib. The results showed no significant differences in gender, age, marital status, occupation, and education level between patients with and without cytopenia. Multivariable analysis revealed that baseline anemia, neutropenia, thrombocytopenia, and thrombocytosis increased the odds of developing cytopenia.
Article
Pharmacology & Pharmacy
Congying Gao, Lei Zhang, Yun Xu, Xiangyu Ma, Peilei Chen, Zhe-Sheng Chen, Liuya Wei
Summary: In this study, the potent histone deacetylase inhibitor I13 was assessed for its effect on chronic myeloid leukemia (CML) cells harboring T315I-mutated and wild-type BCR-ABL. I13 showed strong activity against both types of cells, inducing cell differentiation and suppressing proliferation by causing cell cycle G0/G1-phase accumulation. It was found that I13 blocked the CML signaling pathway by depleting BCR-ABL, resulting in cell differentiation. These findings highlight I13 as a BCR-ABL modulator for overcoming drug resistance caused by T315I-mutated BCR-ABL and have implications for CML therapy development.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Elena Vuelta, Jose L. Ordonez, David J. Sanz, Sandra Ballesteros, Jesus M. Hernandez-Rivas, Lucia Mendez-Sanchez, Manuel Sanchez-Martin, Ignacio Garcia-Tunon
Summary: This study demonstrates the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms. The CRISPR-Trap efficiently interrupts the coding sequence of the oncogene and allows for the selection of edited cells. In vitro and in vivo experiments show the therapeutic benefit of this system.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Shohei Kawakami, Mitsuyo Tsuma-Kaneko, Masakazu Sawanobori, Tomoko Uno, Yoshihiko Nakamura, Hideyuki Matsuzawa, Rikio Suzuki, Makoto Onizuka, Takashi Yahata, Kazuhito Naka, Kiyoshi Ando, Hiroshi Kawada
Summary: This study found that pterostilbene has significant antileukemic effects and can induce apoptosis in leukemic cells, especially in those with the BCR/ABL fusion gene. Pterostilbene also downregulated the BCR/ABL fusion protein levels and suppressed AKT and NF-kappa B activation in BCR/ABL(+) leukemic cells.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Ting-Ting Huang, Xin Wang, Shao-Jia Qiang, Zhen-Nan Zhao, Zhuo-Xun Wu, Charles R. Ashby, Jia-Zhong Li, Zhe-Sheng Chen
Summary: The study identified a potential BCR-ABL inhibitor, ZINC21710815, through drug design and screening, which effectively inhibited the proliferation of different types of leukemia cells, inducing cell cycle arrest and apoptosis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
You-lu Pan, Shen-xin Zeng, Rong-rong Hao, Mei-hao Liang, Zheng-rong Shen, Wen-hai Huang
Summary: This review summarizes the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML, including first, second, and third-generation tyrosine kinase inhibitors targeting different mutations, as well as allosteric inhibitors and proteolysis-targeting chimeras (PROTAC) based on different E3 ligands.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Daisuke Koyama, Jiro Kikuchi, Yoshiaki Kuroda, Masatsugu Ohta, Yusuke Furukawa
Summary: This study reveals the critical role of metabolic homeostasis in the survival of CML cells, particularly in advanced stages of the disease. The BCR-ABL protein activates AMP-activated protein kinase and the mTOR pathway to regulate ATP production and autophagy, with nuclear BCR-ABL detected in advanced-stage CML cells. Activation of AMPK triggers autophagy under energy-deprived conditions, leading to cytoplasmic translocation of BCR-ABL and eventual apoptotic cell death when intracellular ATP is exhausted. This pathway represents a novel therapeutic vulnerability for treating TKI-resistant CML.
Review
Oncology
Priyanka Singh
Summary: This study identified 111 miRNAs that potentially target the PI3K/Akt/mTOR pathway, and selected seven miRNAs for further investigation. Except for hsa-miR-199a-3p, the other six miRNAs have been extensively studied in AML. Given the similarity between AML and CML, these miRNAs may also be advantageous for treating chemoresistance in CML.
Article
Pharmacology & Pharmacy
Huamin Liang, Fengming Zou, Liyi Fu, Qingwang Liu, Beilei Wang, Xiaofei Liang, Jing Liu, Qingsong Liu
Summary: Drug nanocrystals, a common drug delivery system, have the potential to enhance the delivery of poorly water-soluble drugs. However, their rapid clearance and uncontrolled drug release limit their effectiveness. In this study, an amphiphilic co-polymer was synthesized as a stabilizer to fabricate high-drug-loading nanocrystal micelles. These micelles exhibited small size, high drug loading, and controlled release in vitro, as well as long circulation and high drug accumulation in vivo. This research provides new possibilities for the development of more efficient nanocrystal-based injection formulations and the potential clinical application of a CML candidate drug.
Article
Cell Biology
Chang Liu, Waiyi Zou, Danian Nie, Shuyi Li, Chen Duan, Min Zhou, Peilong Lai, Shengyong Yang, Sen Ji, Yangqiu Li, Mei Mei, Shilai Bao, Yanli Jin, Jingxuan Pan
Summary: This study investigates the role of PRMT family member PRMT7 in the maintenance of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). The research shows that targeting PRMT7 delays leukemia development and impairs self-renewal of LSCs without affecting normal hematopoiesis. Mechanistically, loss of PRMT7 leads to reprogramming of glycine metabolism, generating methylglyoxal which is detrimental to LSCs. These findings suggest PRMT7 as a potential therapeutic target for eradicating LSCs in CML.
Article
Pharmacology & Pharmacy
Hong Zhang, Ting Song, Ziqian Wang, Yafei Guo, Hang Wang, Qishuang Gao, Zhichao Zhang, Uwituze Laura Bonneete
Summary: By using a specific inhibitor of Hsp70/Bim complex and knocking down Bcr-Abl, researchers have found that Bcr-Abl can prevent cell apoptosis by driving the formation of Hsp70/Bim complex. Additionally, Bcr-Abl can stabilize oncogenic clients by driving the formation of Hsp70/Bim complex.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Luca Pozzetti, Roberta Ibba, Sara Rossi, Orazio Taglialatela-Scafati, Donatella Taramelli, Nicoletta Basilico, Sarah D'Alessandro, Silvia Parapini, Stefania Butini, Giuseppe Campiani, Sandra Gemma
Summary: The potential of natural and synthetic chalcones as therapeutic leads against various diseases has been explored, and they have shown interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. This study focuses on investigating the anti-leishmanial activity of natural chalcone lophirone E and its derivatives. The synthesis of lophirone E and a small set of chalcones with different substitution patterns has been described, and the compounds were evaluated for their activity against Leishmania infantum promastigotes. The study highlights the potential of this class of compounds as antiparasitic hits and suggests further investigation.
Review
Cell Biology
Alessandro Papa, Silvia Pasquini, Chiara Contri, Sandra Gemma, Giuseppe Campiani, Stefania Butini, Katia Varani, Fabrizio Vincenzi
Summary: Polypharmacology challenges the traditional paradigm of one-drug, one target, one disease by using multitarget compounds for the treatment of complex diseases. The endocannabinoid system is an attractive therapeutic target in central nervous system disorders and neurodegenerative diseases.
Article
Chemistry, Medicinal
Nicola Relitti, A. Prasanth Saraswati, Gabriele Carullo, Alessandro Papa, Alessandra Monti, Rosaria Benedetti, Eugenia Passaro, Simone Brogi, Vincenzo Calderone, Stefania Butini, Sandra Gemma, Lucia Altucci, Giuseppe Campiani, Nunzianna Doti
Summary: In this study, a series of peptide-based Pin1 inhibitors were developed and the compound 5 k demonstrated higher binding affinity to Pin1. Comparative analysis of molecular models identified chemical elements that may enhance inhibitory potency, pharmacological properties, and selectivity of future peptide-based Pin1 inhibitors. Furthermore, conjugation of 5 k with R8 resulted in the derivative R8-5 k, which exhibited antiproliferative effects on cancer cell lines.
Article
Chemistry, Medicinal
Giuseppe Campiani, Tuhina Khan, Cristina Ulivieri, Leopoldo Staiano, Chiara Papulino, Stefania Magnano, Seema Nathwani, Anna Ramunno, Daniel Lucena-Agell, Nicola Relitti, Stefano Federico, Luca Pozzetti, Gabriele Carullo, Alice Casagni, Simone Brogi, Francesca Vanni, Paola Galatello, Magda Ghanim, Niamh McCabe, Stefania Lamponi, Massimo Valoti, Ola Ibrahim, Jeffrey O'Sullivan, Richard Turkington, Vincent P. Kelly, Ruben VanWemmel, J. Fernando Diaz, Sandra Gemma, Daniela Zisterer, Lucia Altucci, Antonella De Matteis, Stefania Butini, Rosaria Benedetti
Summary: Autophagy, a crucial mechanism for maintaining organismal homeostasis, has become a focus in cancer therapy. In this study, new multifunctional agents with both pro-apoptotic and autophagy-inhibiting effects were designed and their therapeutic potential was demonstrated through experiments.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Alessandra Monti, Raffaele Ronca, Giuseppe Campiani, Menotti Ruvo, Nunzianna Doti
Summary: In this study, the expression of Par17 protein in E. coli cells was evaluated and compared with other Parvulins. The protein was characterized by various techniques, and a new method for determining enzyme activity was developed. The results showed that the protein was well-folded and active, which is of great significance for the study of Parvulins.
MOLECULAR BIOTECHNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Simone Brogi, Roberta Ibba, Sara Rossi, Stefania Butini, Vincenzo Calderone, Sandra Gemma, Giuseppe Campiani
Summary: The nitrile group plays an important role in drug discovery as it can form both non-covalent and covalent interactions with biological targets. It is a mild electrophilic warhead, making it safer and easier to use in the development of drugs. Covalent inhibition is a design approach that mimics the hydrolysis mechanism of proteases, and the nitrile group has been successfully used as an electrophilic warhead in protease inhibitors. The cysteine protease is particularly targeted due to its crucial role in the survival and replication of infective agents.
Article
Cell Biology
Laura Bergantini, Miriana d'Alessandro, Sara Gangi, Dalila Cavallaro, Giuseppe Campiani, Stefania Butini, Claudia Landi, Luca Bini, Paolo Cameli, Elena Bargagli
Summary: This article introduces a new method for isolating and culturing fibroblasts from IPF. The isolated cells exhibit typical fibroblast/myofibroblast characteristics and show high expression of ROS. This method provides a large sample of patients and a reliable model for testing molecules and developing therapeutic targets.
Article
Biochemistry & Molecular Biology
Luca Pozzetti, Francesca Ferrara, Ludovica Marotta, Sandra Gemma, Stefania Butini, Mascia Benedusi, Fabio Fusi, Amer Ahmed, Serena Pomponi, Stefano Ferrari, Matteo Perini, Anna Ramunno, Giacomo Pepe, Pietro Campiglia, Giuseppe Valacchi, Gabriele Carullo, Giuseppe Campiani
Summary: This study evaluated the nutraceutical properties of autochthonous Tuscany EVOO and found promising anti-inflammatory and vasorelaxant effects.
Article
Chemistry, Medicinal
Stefano Federico, Tuhina Khan, Anna Fontana, Simone Brogi, Rosaria Benedetti, Federica Sarno, Gabriele Carullo, Alex Pezzotta, Akella Prasanth Saraswati, Eugenia Passaro, Luca Pozzetti, Alessandro Papa, Nicola Relitti, Sandra Gemma, Stefania Butini, Anna Pistocchi, Anna Ramunno, Fabrizio Vincenzi, Katia Varani, Vanessa Tatangelo, Laura Patrussi, Cosima T. Baldari, Simona Saponara, Beatrice Gorelli, Stefania Lamponi, Massimo Valoti, Fulvio Saccoccia, Marialaura Giannaccari, Giovina Ruberti, Daniel Herp, Manfred Jung, Lucia Altucci, Giuseppe Campiani
Summary: The search for new therapeutic tools for cancer treatment is a challenging task for medicinal chemists. Histone deacetylase (HDAC) enzymes, particularly HDAC6 and HDAC8, are valuable targets in this regard. A study has developed polypharmacological agents that inhibit both hHDAC6 and hHDAC8, which shows potential for the treatment of cancer. These compounds demonstrate nanomolar inhibitory potency against the targeted enzymes and exhibit selectivity in their action.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Fulvio Saccoccia, Luca Pozzetti, Roberto Gimmelli, Stefania Butini, Alessandra Guidi, Giuliana Papoff, Marialaura Giannaccari, Simone Brogi, Viviana Scognamiglio, Sandra Gemma, Giovina Ruberti, Giuseppe Campiani
Summary: Parasitic diseases, such as schistosomiasis, pose a significant global health burden, particularly in impoverished regions. A study has identified two novel schistosomicidal spiroindoline derivatives that can selectively inhibit the activity of the schistosome enzyme HDAC8, paving the way for the development of improved HDAC8-selective allosteric inhibitors. This finding is important for the development of new treatments for parasitic diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Gabriele Carullo, Simona Saponara, Amer Ahmed, Beatrice Gorelli, Sarah Mazzotta, Alfonso Trezza, Beatrice Gianibbi, Giuseppe Campiani, Fabio Fusi, Francesca Aiello
Summary: The labdane scaffold presents a valuable starting point for the development of new vasorelaxant agents. The study reveals the regulatory effects of labdane-type compounds on ion channels and provides a molecular basis for their activity.
Article
Chemistry, Medicinal
Theo Battista, Stefano Federico, Simone Brogi, Luca Pozzetti, Tuhina Khan, Stefania Butini, Anna Ramunno, Eleonora Fiorentino, Stefania Orsini, Trentina Di Muccio, Annarita Fiorillo, Cecile Exertier, Daniel Di Risola, Andrea Ilari, Giuseppe Campiani, Gianni Colotti, Sandra Gemma
Summary: Leishmania spp. is a significant public health issue, and developing better therapeutic drugs is urgently needed. This study optimized a novel class of Leishmania inhibitors through various approaches and identified potent and selective compounds that could be used for treating leishmaniasis and related diseases.
ACS INFECTIOUS DISEASES
(2022)
Article
Oncology
Patricia Hannon Barroeta, Maureen J. O'Sullivan, Daniela M. Zisterer
Summary: Malignant rhabdoid tumour (MRT), a rare and aggressive childhood malignancy, is highly resistant to chemotherapy. This study investigates the role of the antioxidant defense system involving glutathione (GSH) and Nrf2 in MRT cells' response to cisplatin treatment. Results suggest that targeting the Nrf2/GSH antioxidant system may be a potential therapeutic strategy to overcome chemoresistance in rhabdoid tumours.
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
(2023)
Article
Chemistry, Medicinal
Gabriele Carullo, Sarah Mazzotta, Jessica Ceramella, Domenico Iacopetta, Anna Ramunno, Camillo Rosano, Antonella Brizzi, Giuseppe Campiani, Francesca Aiello, Maria S. Sinicropi
Summary: Topoisomerases play a significant role in cancer development and progression in the human body. In particular, the inhibition of topoI has been found to be an effective strategy in controlling cancer cell proliferation. Pyrrole-based compounds have emerged as promising anticancer agents, especially for breast cancer therapy and topoI inhibition. A small library of 1-(2-aminophenyl)pyrrole-based amides (7a-f) has been developed, showing potential as new anticancer agents through their ability to induce apoptosis in MDA-MB-231 cells. Enzymatic assays and docking simulations revealed the inhibitory activity and potential binding site for these compounds.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Shu Wang, Azizah M. Malebari, Thomas F. Greene, Shubhangi Kandwal, Darren Fayne, Seema M. Nathwani, Daniela M. Zisterer, Brendan Twamley, Niamh M. O'Boyle, Mary J. Meegan
Summary: A series of novel analogues of combretastatin A-4 were designed and synthesised as colchicine-binding site inhibitors. These compounds showed significant antiproliferative activities in breast cancer cells and inhibited tubulin assembly. Compound 9q was found to target tubulin, resulting in cellular apoptosis and mitotic catastrophe in MCF-7 cells. In silico molecular docking supported the interaction between the compounds and the colchicine-binding domain of tubulin. Compound 9q has potential as a lead compound for the development of new antitumour agents.
