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Tyrosine kinase inhibitors

Fausto Castagnetti, Francesco Di Raimondo, Antonio De Vivo, Antonio Spitaleri, Gabriele Gugliotta, Francesco Fabbiano, Isabella Capodanno, Donato Mannina, Marzia Salvucci, Agostino Antolino, Roberto Marasca, Maurizio Musso, Monica Crugnola, Stefana Impera, Elena Trabacchi, Caterina Musolino, Francesco Cavazzini, Giuseppe Mineo, Patrizia Tosi, Carmela Tomaselli, Michele Rizzo, Sergio Siragusa, Miriam Fogli, Riccardo Ragionieri, Alessandro Zironi, Simona Soverini, Giovanni Martinelli, Michele Cavo, Paolo Vigneri, Fabio Stagno, Gianantonio Rosti, Michele Baccarani
Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist and the treatment outcome does not only depend on the choice of first-line TKI, but also on second- and third-line TKIs...
October 22, 2016: American Journal of Hematology
Shuhang Wang, Yongping Song, Feifei Yan, Delong Liu
The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9-13 months of therapy...
October 21, 2016: Frontiers of Medicine
Jing Zhao, Xin Ye, Yan Xu, Minjiang Chen, Wei Zhong, Yun Sun, Zhenfan Yang, Guanshan Zhu, Yi Gu, Mengzhao Wang
PURPOSE: Central nervous system (CNS) is the prevalent site for metastases in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-relapsed NSCLC patients. To understand the EGFR mutation status in paired cerebrospinal fluid (CSF) and plasma samples after EGFR-TKI treatment failure might be useful to guide the treatment of intra- and extracranial tumors in those patients. METHODS: Paired CSF and plasma samples were collected from seven NSCLC patients with CNS metastases after EGFR-TKI failure...
October 21, 2016: Cancer Chemotherapy and Pharmacology
Clement Chung
PURPOSE: Current strategies for managing neuroendocrine tumors (NETs) in adult patients are reviewed, with a focus on medication safety concerns. SUMMARY: NETs usually originate in the gastrointestinal or bronchopulmonary tract. Symptoms due to hormonal hypersecretion often occur in patients with foregut or midgut NETs or liver metastases. Surgical resection is recommended for most localized NETs, while systemic cytotoxic chemotherapy is typically used for high-grade and pancreatic tumors...
November 1, 2016: American Journal of Health-system Pharmacy: AJHP
Mei Han, Chengyan Wang, Yinchun Ji, Zilan Song, Li Xing, Yi Su, Xisheng Wang, Ao Zhang, Jing Ai, Meiyu Geng
A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor...
October 14, 2016: Bioorganic & Medicinal Chemistry Letters
Elizabeth E Hjort, Weiqi Huang, Liping Hu, Elizabeth A Eklund
Icsbp/Irf8 is an interferon regulatory transcription factor that functions as a suppressor of myeloid leukemias. Consistent with this activity, Icsbp represses a set of genes encoding proteins that promote cell proliferation/survival. One such gene encodes Gas2, a calpain inhibitor. We previously found that increased Gas2-expression in Bcr-abl+ cells stabilized βcatenin; a Calpain substrate. This was of interest, because βcatenin contributes to disease progression in chronic myeloid leukemia (CML). Calpain has additional substrates implicated in leukemogenesis, including Stat5...
October 19, 2016: Oncotarget
Kristina R Kesely, Antonella Pantaleo, Francesco M Turrini, Peter Olupot-Olupot, Philip S Low
With half of the world's population at risk for malaria infection and with drug resistance on the rise, the search for mutation-resistant therapies has intensified. We report here a therapy for Plasmodium falciparum malaria that acts by inhibiting the phosphorylation of erythrocyte membrane band 3 by an erythrocyte tyrosine kinase. Because tyrosine phosphorylation of band 3 causes a destabilization of the erythrocyte membrane required for parasite egress, inhibition of the erythrocyte tyrosine kinase leads to parasite entrapment and termination of the infection...
2016: PloS One
Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
Daniel M Czyż, Neeta Jain-Gupta, Howard A Shuman, Sean Crosson
Brucella abortus is an intracellular bacterial pathogen and an etiological agent of the zoonotic disease known as brucellosis. Brucellosis can be challenging to treat with conventional antibiotic therapies and, in some cases, may develop into a debilitating and life-threatening chronic illness. We used multiple independent assays of in vitro metabolism and intracellular replication to screen a library of 480 known bioactive compounds for novel B. abortus anti-infectives. Eighteen non-cytotoxic compounds specifically inhibited B...
October 21, 2016: Scientific Reports
Sarah Elizabeth Skerratt, Mark D Andrews, Sharan K Bagal, James Bilsland, David Brown, Peter J Bungay, Susan Cole, Karl R Gibson, Russell Jones, Inaki Morao, Angus Nedderman, Kiyoyuki Omoto, Colin Robinson, Thomas Ryckmans, Kimberly Skinner, Paul Anthony Stupple, Gareth Waldron
The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention...
October 21, 2016: Journal of Medicinal Chemistry
Apirat Chaikuad, Julien Diharce, Martin Schröder, Alicia Foucourt, Bertrand Leblond, Anne-Sophie Casagrande, Laurent Desire, Pascal Bonnet, Stefan Knapp, Thierry Besson
Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a non-canonical binding mode of compound 1 and 2 in DYRK2 explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinase...
October 21, 2016: Journal of Medicinal Chemistry
Shuyang Yao, Xiuyi Zhi, Ruotian Wang, Kun Qian, Mu Hu, Yi Zhang
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non-small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR-mutated NSCLC patients undergoing resection of stage IB-IIIA. METHODS: Our retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy...
September 2016: Thoracic Cancer
Aimi Huang, Rong Li, Jikai Zhao, Xiaofei Wang, Bo Jin, Yanjie Niu, Jie Zhang, Liyan Jiang, Baohui Han
This article demonstrates a case of a lung adenocarcinoma patient in stage IV harboring an epidermal growth factor receptor (EGFR) 19 exon deletion mutation treated with 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on day 1, sequenced with 250 mg gefitinib on prescription on days 4-28 for six cycles as first-line, then by gefitinib combined with pemetrexed as maintenance therapy. The patient achieved a partial response. Performance status increased from grade 2 to 1. The progression-free survival period was 17 months...
September 2016: Thoracic Cancer
Vincent Yi-Fong Su, Chia-Jen Liu, Yuh-Min Chen, Teh-Ying Chou, Tzeng-Ji Chen, Sang-Hue Yen, Tzeon-Jye Chiou, Jin-Hwang Liu, Yu-Wen Hu
BACKGROUND: Currently, no large study addressing the relationship between lung cancer patients with different therapies and second primary malignancies (SPMs) is available. METHODS: Using the Taiwan National Health Insurance Research Database, we conducted a population-based cohort study. Patients with newly diagnosed lung cancer between 1997 and 2005 were enrolled and followed up until Dec. 31, 2011. The endpoint of the study was SPM occurrence. Standardized incidence ratios (SIRs) of cancers were calculated to compare the cancer incidence of the study cohort to that of the general population...
October 20, 2016: Targeted Oncology
Chee Khoon Lee, Johnathan Man, Sally Lord, Matthew Links, Val Gebski, Tony Mok, James Chih-Hsin Yang
INTRODUCTION: We performed a meta-analysis to assess the role of immune-checkpoint inhibitors as second-line therapy in epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC). METHODS: Randomized trials comparing immune-checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation defined subgroups...
October 17, 2016: Journal of Thoracic Oncology
Susan M Farabaugh, Bonita T Chan, Xiaojiang Cui, Robert K Dearth, Adrian V Lee
BACKGROUND: ErbB2 Receptor Tyrosine Kinase 2 (ErbB2, HER2/Neu) is amplified in breast cancer and associated with poor prognosis. Growing evidence suggests interplay between ErbB2 and insulin-like growth factor (IGF) signaling. For example, ErbB2 inhibitors can block IGF-induced signaling while, conversely, IGF1R inhibitors can inhibit ErbB2 action. ErbB receptors can bind and phosphorylate insulin receptor substrates (IRS) and this may be critical for ErbB-mediated anti-estrogen resistance in breast cancer...
October 21, 2016: Cell Communication and Signaling: CCS
Marc A Becker, Xiaonan Hou, Piyawan Tienchaianada, Brian B Haines, Sean C Harrington, S John Weroha, Sriram Sathyanarayanan, Paul Haluska
BACKGROUND: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERα) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years...
October 20, 2016: BMC Cancer
Antonin Levy, Etienne Bardet, Benjamin Lacas, Jean-Pierre Pignon, Julien Adam, Ludovic Lacroix, Xavier Artignan, Pierre Verrelle, Cécile Le Péchoux
BACKGROUND: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer. PATIENTS AND METHODS: This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status...
October 18, 2016: Oncotarget
Hye Seon Kang, Chin Kook Rhee, Hea Yon Lee, Hyoung Kyu Yoon, Soon Seok Kwon, Sook Young Lee
Background/Aims: Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling...
October 20, 2016: Korean Journal of Internal Medicine
Dariusz Wodziak, Aiwen Dong, Michael F Basin, Anson W Lowe
A recently published study identified Anterior Gradient 2 (AGR2) as a regulator of EGFR signaling by promoting receptor presentation from the endoplasmic reticulum to the cell surface. AGR2 also promotes tissue regeneration in amphibians and fish. Whether AGR2-induced EGFR signaling is essential for tissue regeneration in higher vertebrates was evaluated using a well-characterized murine model for pancreatitis. The impact of AGR2 expression and EGFR signaling on tissue regeneration was evaluated using the caerulein-induced pancreatitis mouse model...
2016: PloS One
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