Review
Biochemistry & Molecular Biology
Mai Tanaka, Dietmar W. Siemann
Summary: Dysregulated signaling pathways in cancer cells and the tumor microenvironment, including the Axl and Gas6 pathways, have led to the development of therapeutic agents targeting the Gas6/Axl pathway. Promising results have been observed in both preclinical and clinical settings, indicating potential clinical efficacy of targeting Gas6 and Axl.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Gastroenterology & Hepatology
Lorenza Rimassa, Richard S. Finn, Bruno Sangro
Summary: Single-agent immune checkpoint inhibitors (ICIs) have limited efficacy in advanced hepatocellular carcinoma (HCC) patients, and approximately 30% of patients show intrinsic resistance to ICIs. Therefore, researchers are exploring combination therapies, such as anti-angiogenic agents and other ICIs. Some trials have shown promising results and potential for clinical application. However, there are still many unanswered questions that require further research.
JOURNAL OF HEPATOLOGY
(2023)
Article
Chemistry, Medicinal
Rui He, Zhiqiang Song, Yu Bai, Sheng He, Jing Huang, Yongxing Wang, Fengtao Zhou, Weixue Huang, Jing Guo, Zhen Wang, Zheng-Chao Tu, Xiaomei Ren, Zhang Zhang, Jian Xu, Ke Ding
Summary: AXL kinase is crucially involved in cancer tumorigenesis, metastasis, and drug resistance, and multiple AXL inhibitors are currently being investigated in clinical trials. Recent research has highlighted the importance of the N-terminal region of AXL in cell invasiveness, suggesting that targeting AXL degradation could be a more effective therapeutic approach compared to kinase inhibitors. In this study, a series of new AXL PROTAC degraders were discovered, with compound 6n emerging as a potent AXL depletor in TNBC cells. It exhibited superior inhibitory effects on AXL signaling activation, cell proliferation, migration, and invasion compared to the corresponding kinase inhibitor. Additionally, compound 6n showed promising therapeutic potential in patient-derived organoids and a mouse model of MDA-MB-231 cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Heidi M. Haikala, Pasi A. Janne
Summary: HER3, a pseudokinase member of the EGFR family, plays a crucial role in tumor progression and drug resistance. Despite being discovered over 30 years ago, therapeutic interventions targeting HER3 have not yet received clinical approval, leading to increasing preclinical and clinical trials.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Ashish Noronha, Nishanth Belugali Nataraj, Joo Sang Lee, Benny Zhitomirsky, Yaara Oren, Sara Oster, Moshit Lindzen, Saptaparna Mukherjee, Rainer Will, Soma Ghosh, Arturo Simoni-Nieves, Aakanksha Verma, Rishita Chatterjee, Simone Borgoni, Welles Robinson, Sanju Sinha, Alexander Brandis, D. Lucas Kerr, Wei Wu, Arunachalam Sekar, Suvendu Giri, Youngmin Chung, Diana Drago-Garcia, Brian P. Danysh, Mattia Lauriola, Michelangelo Fiorentino, Andrea Ardizzoni, Moshe Oren, Collin M. Blakely, Jideofor Ezike, Stefan Wiemann, Laxmi Parida, Trever G. Bivona, Rami Aqeilan, Joan S. Brugge, Aviv Regev, Gad Getz, Eytan Ruppin, Yosef Yarden
Summary: EGFR inhibitors activate endogenous mutators in lung cancer cells, leading to drug resistance. Inhibiting this process can prevent drug resistance.
Article
Multidisciplinary Sciences
Marta Nyakas, Karianne Giller Fleten, Mads Haugland Haugen, Nikolai Engedal, Christina Sveen, Inger Nina Farstad, Vivi Ann Florenes, Lina Prasmickaite, Gunhild Mari Maelandsmo, Kotryna Seip
Summary: This study investigated the therapeutic potential of combining an AXL inhibitor (AXLi) and a clinically relevant BRAF inhibitor (BRAFi) for the treatment of metastatic melanoma. The results showed that AXL was expressed in the majority of melanoma lymph node metastases. In vitro experiments demonstrated that the combination of AXLi and BRAFi resulted in the largest reduction in cell viability. Moreover, pre-clinical studies using AXL(high) melanoma models showed a therapeutic benefit of adding AXLi to the BRAF-targeted therapy. Mechanistic insights revealed that AXLi potentiated BRAFi-induced apoptosis, stimulated ferroptosis, and inhibited autophagy. Overall, this study suggests that combining AXLi with standard therapy could improve the therapeutic outcome in metastatic melanoma.
SCIENTIFIC REPORTS
(2022)
Review
Oncology
Andrew H. Lipsky, Nicole Lamanna
Summary: Targeted therapies have revolutionized the frontline treatment for CLL, reducing reliance on chemoimmunotherapy. Drugs such as ibrutinib, acalabrutinib, and venetoclax have shown efficacy in oral therapy. This review explores novel therapeutic strategies using these agents in combination, highlighting the importance of patient characteristics and study methodology.
Review
Pharmacology & Pharmacy
Yazan Haddad, Marek Remes, Vojtech Adam, Zbynek Heger
Summary: The study utilized variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. These families shared similar mutational profiles, ligand R-groups facing the C-helix, mutation sites, and DFG domain.
DRUG DISCOVERY TODAY
(2021)
Article
Biochemistry & Molecular Biology
Summer Sofer, Kevin Lamkiewicz, Shir Armoza Eilat, Shirly Partouche, Manja Marz, Neta Moskovits, Salomon M. Stemmer, Amir Shlomai, Ella H. Sklan
Summary: This study identified Hexokinase 1 (HK1) as a top candidate gene associated with tyrosine-kinase inhibitor (TKI) resistance in hepatoma cells. HK1 expression was upregulated in regorafenib-resistant cells, and an HK inhibitor resensitized resistant cells to TKI treatment. These findings suggest that HK1 may serve as a biomarker for treatment success in hepatocellular carcinoma.
Article
Oncology
Kristina Breitenecker, Viola Hedrich, Franziska Pupp, Doris Chen, Eva Reznickova, Gregor Ortmayr, Heidemarie Huber, Gerhard Weber, Lorenz Balcar, Matthias Pinter, Wolfgang Mikulits
Summary: The study reveals that HCC cells with a mesenchymal-like phenotype are less sensitive to drug treatment, linking TKI resistance to changes in epithelial plasticity.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
Pasi A. Janne, Christina Baik, Wu-Chou Su, Melissa L. Johnson, Hidetoshi Hayashi, Makoto Nishio, Dong-Wan Kim, Marianna Koczywas, Kathryn A. Gold, Conor E. Steuer, Haruyasu Murakami, James Chih-Hsin Yang, Sang-We Kim, Michele Vigliotti, Rong Shi, Zhenhao Qi, Yang Qiu, Lihui Zhao, David Sternberg, Channing Yu, Helena A. Yu
Summary: HER3-DXd shows clinical activity in EGFR TKI-resistant lung cancer, regardless of resistance mechanisms, providing a new approach to treat drug-resistant cancers.
Article
Chemistry, Medicinal
Jingru Qiu, Qinghong Liu, Peixia Li, Qiaoyun Jiang, Weijia Chen, Donghai Li, Guiling Li, Gang Shan
Summary: This work presents a photocatalytic approach called ligand-directed photodegradation of interacting proteins (LDPIP) for efficient degradation of protein-protein heterodimers. LDPIP utilizes a photosensitizing protein ligand, appropriate light, and molecular oxygen to induce oxidative damage to both the ligand-binding protein and its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was designed based on the FDA-approved HER2 inhibitor lapatinib to degrade HER2 and its difficult-to-target interacting protein partner HER3. HER-PS-I exhibited excellent anticancer activity in drug-resistant MDA-MB-453 cells and multicellular spheroids. The LDPIP approach holds promise for degrading undruggable or difficult-to-drug proteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Shingpan Chan, Yunong Zhang, Jie Wang, Qiuchun Yu, Xia Peng, Jian Zou, Licheng Zhou, Li Tan, Yunxin Duan, Yang Zhou, Hoon Hur, Jing Ai, Zhen Wang, Xiaomei Ren, Zhang Zhang, Ke Ding
Summary: The study describes the discovery of 3-aminopyrazole derivatives as potent and selective AXL kinase inhibitors. One representative compound, 6li, showed strong inhibitory activity against AXL enzymatic activity and demonstrated significant antitumor efficacy in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Editorial Material
Genetics & Heredity
Ivona Aksentijevich
Summary: Immune responses require a delicate balance - too weak or too strong a response can cause issues. Spleen tyrosine kinase plays a crucial role in multiple signaling pathways, and its gain-of-function alterations can lead to various problems, including hypogammaglobulinemia and predisposition to B cell lymphoma.
Article
Cell Biology
Pardis Mohammadzadeh, Mina Roueinfar, Gregory C. Amberg
Summary: This study reveals a novel role for AXL as a modulator of GnRH receptor signaling. Gas6 enhances GnRH-dependent ERK phosphorylation and Egr-1 transcript abundance, and promotes LH beta production and pro-MMP9 protein generation, as well as cell migration.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Pharmacology & Pharmacy
Anita Artarini, Michael Meyer, Yu Jin Shin, Kilian Huber, Nikolaus Hilz, Franz Bracher, Daniel Eros, Laszlo Orfi, Gyorgy Keri, Sigrid Goedert, Martin Neuenschwander, Jens von Kries, Yael Domovich-Eisenberg, Noa Dekel, Istvan Szabadkai, Mario Lebendiker, Zoltan Horvath, Tsafi Danielie, Oded Livnahe, Olivier Moncorge, Rebecca Frise, Wendy Barclay, Thomas F. Meyer, Alexander Karlas
ANTIVIRAL RESEARCH
(2019)
Article
Multidisciplinary Sciences
Gyula Bencze, Szilvia Bencze, Keith D. Rivera, James D. Watson, Laszlo Orfi, Nicholas K. Tonks, Darryl J. Pappin
SCIENTIFIC REPORTS
(2020)
Correction
Multidisciplinary Sciences
Gyula Bencze, Szilvia Bencze, Keith D. Rivera, James D. Watson, Mate Hidvegi, Laszlo Orfi, Nicholas K. Tonks, Darryl J. Pappin
Summary: A correction to this paper has been published and readers can access it through the link at the top of the paper.
SCIENTIFIC REPORTS
(2021)
Article
Biochemistry & Molecular Biology
Agnes Molnar, Tamas Lakat, Adam Hosszu, Beata Szebeni, Anna Balogh, Laszlo Orfi, Attila J. Szabo, Andrea Fekete, Judit Hodrea
Summary: This study provides lyophilization protocols for various rat and mouse tissues, demonstrating the long-term stability of lyophilized samples and the preservation of protein and RNA quality. By concentrating biological solutions and accurately measuring water content, more reliable data sources are provided for research.
Article
Multidisciplinary Sciences
Zoltan-Istvan Szabo, Gyorgy Orban, Eniko Borbas, Dora Csicsak, Szabina Kadar, Bela Fiser, Mate Dobo, Peter Horvath, Eszter Kiss, Livia Budai, Judit Dobos, Tamas Palla, Laszlo Orfi, Gergely Volgyi, Gergo Toth
Summary: The inclusion complexation of pomalidomide with sulfobutylether-beta-cyclodextrin significantly enhances the water solubility of pomalidomide and maintains its anti-angiogenic activity. Various analytical techniques were employed to characterize the complex, confirming a 1:1 stoichiometry between pomalidomide and sulfobutylether-beta-cyclodextrin.
Article
Biochemistry & Molecular Biology
Apor Veres-Szekely, Domonkos Pap, Beata Szebeni, Laszlo Orfi, Csenge Szasz, Csenge Pajtok, Eszter Levai, Attila J. Szabo, Adam Vannay
Summary: Fibroblasts play a central role in diseases such as idiopathic pulmonary fibrosis. This study developed a cost-effective method to examine fibroblast migration and discussed the advantages of combining different functional assays in drug development.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Valenti Gomez, Myria Galazi, Gregory Weitsman, James Monypenny, Fahad Al-Salemee, Paul R. Barber, Kenrick Ng, Richard Beatson, Balint Szokol, Laszlo Orfi, Greg Mullen, Bart Vanhaesebroeck, Simon Chowdhury, Hing Y. Leung, Tony Ng
Summary: This study investigated the response of PTEN wild-type prostate cancer cells to dual PI3K/mTOR inhibitor treatment and found that combination therapy with HER2 or mGluR1 inhibitors can inhibit cell survival and tumor growth, providing a new therapeutic possibility for patients with PTEN wild-type PI3K/AKT-mutant prostate cancer.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Multidisciplinary Sciences
Gabor Bogal, Jozsef Muranyi, Balint Szokol, Zoltan Kukor, Istvan Mora, Tamas Kardon, Laszlo Orfi, Andras Hrabak
Summary: The aim of this study was to identify new signaling pathways and repolarize macrophages by selected protein kinase inhibitors. Our results suggest that the repolarization of macrophages cannot be achieved by inhibiting their signaling pathways; nevertheless, the expression of certain polarization markers was decreased, therefore a depolarization could be observed both in M1 and M2 polarized cells.
Article
Chemistry, Medicinal
Janos Garai, Balazs Radnai, Eszter Vamos, Dominika Kovacs, Viola Bagone Vantus, Zoltan Rumbus, Eszter Pakai, Andras Garami, Gergely Gulyas-Fekete, Attila Agocs, Marcell Kreko, Khadiza Zaman, Laszlo Prokai, Laszlo Orfi, Peter B. Jakus, Tamas Lorand
Summary: This study reports the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors. Many of these derivatives were effective inhibitors of MIF-tautomerase, with 1-indanone derivatives 16 and 20 being the most potent. Some compounds also acted as selective enolase or ketonase inhibitors. Additionally, several compounds exhibited anti-inflammatory effects and inhibited the production of NO, TNF alpha, and IL-6 in lipopolysaccharide-induced macrophages.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Andras Hrabak, Gabor Bogel, Jozsef Muranyi, Viola Tamasi, Krisztina Nemeth, Balint Szokol, Zoltan Kukor, Tamas Kardon, Laszlo Orfi
Summary: The study aims to reveal the relationship between activation and polarization of rat peritoneal macrophages, detect the involved signaling routes, and find selective protein kinase inhibitors that reduce the production of inflammatory proteins in activated peritoneal macrophages.
MOLECULAR IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Judit Hodrea, Minh Ngoc Tran, Balazs Besztercei, Timea Medveczki, Attila J. Szabo, Laszlo Orfi, Illes Kovacs, Andrea Fekete
Summary: Primary open-angle glaucoma is a global issue without a definitive treatment. Increased intraocular pressure (IOP) is considered a primary risk factor, caused by fibrotic changes in the trabecular meshwork (TM). This study demonstrates that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic effects in TM cells, reducing cell proliferation, migration, and fibrotic protein levels. The S1R protects against fibrosis by increasing nitric oxide production and facilitating extracellular matrix degradation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Bettina Ravai, Nora Popovics-Toth, Kinga Komka, Istvan Csontos, Balint Szokol, Zoltan Orfi, Laszlo Orfi, Erika Balint
Summary: A new multicomponent method was developed for the synthesis of benzo[de]isoquinolinones bearing a phosphonate or a phosphine oxide moiety. The synthesis was carried out under mild conditions and the reaction mechanism and cytotoxicity of the compounds were investigated.
REACTION CHEMISTRY & ENGINEERING
(2023)
Article
Biochemistry & Molecular Biology
Janos Garai, Marcell Kreko, Laszlo Orfi, Peter Balazs Jakus, Zoltan Rumbus, Patrik Keringer, Andras Garami, Eszter Vamos, Dominika Kovacs, Viola Bagone Vantus, Balazs Radnai, Tamas Lorand
Summary: The study shows that certain synthesized tetralones and their derivatives can inhibit MIF's tautomeric functions, regulate macrophage activation, and reduce inflammatory responses.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Gyorgyi A. Nelhubel, Mihaly Cserepes, Balazs Szabo, Dora Turk, Adel Karpati, Istvan Kenessey, Erzsebet Raso, Tamas Barbai, Zita Hegedus, Viktoria Laszlo, Balint Szokol, Judit Dobos, Laszlo Orfi, Jozsef Tovari
Summary: The study demonstrated that HNSCC cell lines expressing the EGFR R521K mutation exhibited resistance to cetuximab therapy, but showed response to treatment with c-MET tyrosine kinase inhibitor SU11274.
PATHOLOGY & ONCOLOGY RESEARCH
(2021)
Article
Neurosciences
Eva Szoke, Monika Balint, Csaba Hetenyi, Adrienn Markovics, Krisztian Elekes, Gabor Pozsgai, Tamas Szuts, Gyorgy Keri, Laszlo Orfi, Zoltan Sandor, Janos Szolcsanyi, Erika Pinter, Zsuzsanna Helyes