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Jak2 inhibitor

Kenta Yagi, Akira Shimada, Toshiaki Sendo
Imatinib (IMA) is the standard treatment for CML; however, stopping IMA sometimes results in disease relapse, which suggests that leukemic stem cells (LSCs) remain in such patients, even after complete molecular remission has been achieved. Therefore, new strategies will be required to eradicate LSCs. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is part of the BCR-ABL signaling network, and it is activated in CML, especially in LSCs. JAK2 is known to be associated with CML survival, but the role of JAK3 in CML remains unknown...
February 16, 2018: European Journal of Pharmacology
Mark Collinge, Douglas J Ball, Christopher J Bowman, Andrea L Nilson, Zaher A Radi, W Mark Vogel
Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed...
February 14, 2018: Regulatory Toxicology and Pharmacology: RTP
Chieyeon Chough, Misuk Joung, Sunmin Lee, Jaemin Lee, Jong Hoon Kim, B Moon Kim
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration...
February 3, 2018: Bioorganic & Medicinal Chemistry
Seung Taek Lim, Ye Won Jeon, Hongki Gwak, Se Young Kim, Young Jin Suh
The Janus kinase (JAK)1 and JAK2 inhibitor, ruxolitinib, and the active form of vitamin D (calcitriol) were previously reported to possess anticancer effects in breast cancer. The present study investigated the combined effects of ruxolitinib and calcitriol on an estrogen receptor (ER)‑positive, human epidermal growth factor receptor 2 (HER2)‑positive, breast cancer cell line. The ER and HER2‑positive MCF7‑HER18 breast cancer cell line was used to investigate the combination effect of ruxolitinib and calcitriol...
February 8, 2018: Molecular Medicine Reports
M -L Nairismägi, M E Gerritsen, Z M Li, G C Wijaya, B K H Chia, Y Laurensia, J Q Lim, K W Yeoh, X S Yao, W L Pang, A Bisconte, R J Hill, J M Bradshaw, D Huang, T L L Song, C C Y Ng, V Rajasegaran, T Tang, Q Q Tang, X J Xia, T B Kang, B T Teh, S T Lim, C K Ong, J Tan
Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Niki Karachaliou, Imane Chaib, Andres Felipe Cardona, Jordi Berenguer, Jillian Wilhelmina Paulina Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Chunping Hu, Ana Drozdowskyj, Carles Codony Servat, Jordi Codony Servat, Masaoki Ito, Ilaria Attili, Erika Aldeguer, Ana Gimenez Capitan, July Rodriguez, Leonardo Rojas, Santiago Viteri, Miguel Angel Molina-Vila, Sai-Hong Ignatius Ou, Morihito Okada, Tony S Mok, Trever G Bivona, Mayumi Ono, Jean Cui, Santiago Ramón Y Cajal, Peng Cao, Rafael Rosell
Epidermal growth factor receptor (EGFR)-mutation-positive non-smallcell lung cancer (NSCLC) is incurable, despite high rates of response to EGFR tyrosine kinase inhibitors (TKIs). We investigated receptor tyrosine kinases (RTKs), Src family kinases and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC. We performed gene expression analysis in two cohorts (Cohort 1 and Cohort 2) of EGFR-mutation-positive NSCLC patients treated with EGFR TKI. We evaluated the efficacy of gefitinib or osimertinib with the Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005 in vitro and in vivo...
February 5, 2018: EBioMedicine
Sonam Sinha, Sonal Sharma, Jaykant Vora, Heta Shah, Anshu Srivastava, Neeta Shrivastava
ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens (L.) DC (MP) is an ancient Indian medicinal plant traditionally used to treat Parkinson's disease. L-Dopa (LD), precursor of dopamine is abundantly found in the seeds of MP. L-dopa is a natural inhibitor of prolactin (PRL) hormone which is required to maintain lactation in women but it's over production (hyperprolactinemia) plays critical role in advancement of breast cancer. AIM OF THE STUDY: We aim to examine the pharmacological effect of LD and MP on this hyperprolactinemia associated breast cancer and related signaling for effective management of the disease...
February 7, 2018: Journal of Ethnopharmacology
Gaetano Sodaro, Elena Cesaro, Giorgia Montano, Giancarlo Blasio, Federica Fiorentino, Simona Romano, Arnaud Jacquel, Patrick Aurberger, Paola Costanzo
The transcription factor ZNF224 plays a key proapoptotic role in chronic myelogenous leukemia (CML), by modulating Wilms Tumor protein 1 (WT1) dependent apoptotic genes transcription. Recently, we demonstrated that Bcr-Abl signaling represses ZNF224 expression in Bcr-Abl positive CML cell lines and in CML patients. Interestingly, Imatinib and second-generation tyrosine kinase inhibitors specifically increase ZNF224 expression. On the other hand, Bcr-Abl positively modulates, via JAK2 activation, the expression of the c-Myc oncogene, which is required for Bcr-Abl oncogenic transformation in CML...
January 9, 2018: Oncotarget
Emma Guttman-Yassky, Jonathan I Silverberg, Osamu Nemoto, Seth B Forman, August Wilke, Randy Prescilla, Amparo de la Peña, Fabio P Nunes, Jonathan Janes, Margaret Gamalo, David Donley, Jim Paik, Amy M DeLozier, Brian J Nickoloff, Eric L Simpson
BACKGROUND: Baricitinib, an oral selective inhibitor of Janus kinase (JAK)1 and JAK2, modulates pro-inflammatory cytokine signaling. OBJECTIVES: The efficacy and safety of baricitinib were evaluated in patients with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 2, randomized, double-blind, placebo-controlled study, 124 patients with moderate-to-severe AD applied topical corticosteroids (TCS) for 4 weeks before randomization to once daily placebo, baricitinib 2 mg, or baricitinib 4 mg for 16 weeks...
February 1, 2018: Journal of the American Academy of Dermatology
Javier Milara, Gracia Hernandez, Beatriz Ballester, Anselm Morell, Inés Roger, P Montero, Juan Escrivá, José M Lloris, Maria Molina-Molina, Esteban Morcillo, Julio Cortijo
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease...
February 6, 2018: Respiratory Research
William Vainchenker, Emilie Leroy, Laure Gilles, Caroline Marty, Isabelle Plo, Stefan N Constantinescu
JAK inhibitors have been developed following the discovery of the JAK2 V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL ) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity...
2018: F1000Research
Jun-Xiu Liu, Wei Chen, Kai-Lin Xu
Myelofibrosis(MF) is a type of myeloprolifirative neoplasms which is difficult to be treated. With the discovery of V617F mutation site in Janus kinase 2 (JAK2), JAK inhibitor provides a new treatment strategy for patients with myelofibrosis. Since 2011 the FDA in USA approved the first generation of JAK inhibitor Ruxolitinib for marketing, a growing number of JAK inhibitors have been entering into the clinical trials and showed a certain clinical efficacy. On the one hand, some JAK inhibitors for single application can effectively relieve the clinical symptoms of patients with myelofibrosis, slow down disease progression, and prolong the survival; on the other hand, JAK inhibitor can also be applied in combination with traditional or other new targeted drugs for MF patients, even during the allogenetic hematopoietic stem cell transplantation, thus providing more choices for targeted therapy on the patients with myelofibrosis...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Xing Song, Yingjie Shao, Tianwei Jiang, Yun Ding, Bin Xu, Xiao Zheng, Qi Wang, Xin Chen, Wendong Gu, Changping Wu, Jingting Jiang
BACKGROUND: In the present study, we aimed to investigate the role of epidermal growth factor receptor (EGFR) pathway in the up-regulation of programmed death ligand-1 (PD-L1) caused by radiotherapy (RT). MATERIALS AND METHODS: Tissue microarrays (TMA) consisting of glioma cancer specimens from 64 patients were used to examine the correlation between PD-L1 and EGFR levels. Furthermore, we performed in vitro experiments to assess the role of EGFR pathway in RT-upregulated PD-L1 expression using human glioma cell lines U87 and U251...
January 30, 2018: EBioMedicine
Jing-Ru Weng, Eman M E Dokla, Li-Yuan Bai, Ching-Shih Chen, Shih-Jiuan Chiu, Tzong-Ming Shieh
5' AMP-activated protein kinase enzyme (AMPK), a master regulator of cellular metabolism, is recognized for its association with various metabolic diseases, inflammation and cancer. In this study, we aimed to investigate the role of compound 59, an AMPK activator, in a panel of oral squamous cell carcinoma (OSCC) cell lines. The anti-proliferative effects of compound 59 were assessed by MTT assays, flow cytometry, western blotting, confocal microscopy and transmission electron microscopy. Relative to OSCC cells, normal human oral keratinocytes were almost insensitive to compound 59 treatment...
February 2, 2018: Basic & Clinical Pharmacology & Toxicology
Suping Guo, Chuanyu Gao, Wentao Xiao, Jing Zhang, Yongsheng Qu, Jiang Li, Famin Ye
Studies have shown that matrine showed cardiovascular protective effects; however, its role and mechanism in myocardial ischemia/reperfusion (I/R) injury remain unknown. The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway activation and elevated heat shock protein (HSP) 70 are closely related to the prevention of myocardial I/R injury. The cardioprotective effects of matrine were determined in hypoxia/reoxygenation (H/R) treated primary rat cardiomyocytes and left anterior descending coronary artery ligation and reperfusion animal models...
February 1, 2018: Shock
Yuquan Wu, Juan Xu, Jing Xu, Wei Zheng, Qingyong Chen, Deming Jiao
The present study aimed to investigate the mechanism by which the Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway mediates cerebral ischemia and the efficacy of pharmaceutical intervention. The rat model of middle cerebral artery occlusion (MCAO) was established and confirmed via assessment of changes in the expression of phosphorylated (p)‑JAK2, p‑STAT3, high‑mobility group box 1 (HMGB1), and inflammatory factors using ELISA and western blot analysis. The effects of JAK2/STAT3 inhibitor and curcumin on the expression of p‑JAK2, p‑STAT3, HMGB1, and inflammatory factors after cerebral ischemia were observed with ELISA, western blotting and immunohistochemical staining...
January 24, 2018: Molecular Medicine Reports
Xing Zhang, Hong Lu, Weilong Hong, Leping Liu, Silu Wang, Mengtao Zhou, Bicheng Chen, Yongheng Bai
Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug‑resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)‑induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA‑resistant cells (PANC‑1‑TSA) had higher proliferative activity than non‑resistant cells (PANC‑1)...
January 31, 2018: Oncology Reports
Refaat A Eid, Mahmoud A Alkhateeb, Samy Eleawa, Fahaid H Al-Hashem, Mubarak Al-Shraim, Attalla Farag El-Kott, Mohamed Samir Ahmed Zaki, Mohammad A Dallak, Hussain Aldera
The molecular mechanisms through which ghrelin exerts its cardioprotective effects during cardiac remodeling post-myocardial infarction (MI) are poorly understood. The aim of this study was to investigate whether the cardioprotection mechanisms are mediated by modulation of JAK/STAT signaling and what triggers this modulation. Rats were divided into six groups (n = 12/group): control, sham, sham + ghrelin (100 µg/kg, s.c., daily, starting 1 day post-MI), MI, MI+ ghrelin, and MI+ ghrelin+ AG490, a potent JAK2 inhibitor (5 mg/kg, i...
February 1, 2018: Basic Research in Cardiology
Won Jin Lee, Sun Ah Ham, Hyunjin Yoo, Jung Seok Hwang, Taesik Yoo, Kyung Shin Paek, Dae-Seog Lim, Sung Gu Han, Chi-Ho Lee, Kwonho Hong, Han Geuk Seo
Neuroinflammation-associated release of glutamate from activated microglia has been implicated in the progression of neurodegenerative diseases. However, the regulatory mechanisms underlying this glutamate release are poorly understood. Here, we show that peroxisome proliferator-activated receptor delta (PPARδ) modulates neurotoxicity by inhibiting glutamate release in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Activation of PPARδ by GW501516, a specific PPARδ agonist, inhibited glutamate release in BV-2 cells...
February 1, 2018: Journal of Cellular Biochemistry
Augusto S Nascimento, Luisa L Peres, Alessandra V S Fari, Renato Milani, Rodrigo A Silva, Celio Jr da Costa Fernandes, Maikel P Peppelenbosch, Carmen V Ferreira-Halder, Willian F Zambuzzi
Breast cancer is responsible for 25% of cancer cases and 15% of cancer death among women. Treatment is usually prolonged and hampered by the development of chemoresistance. The molecular mechanisms maintaining the chemoresistant phenotype remains, however, largely obscure. As kinase signaling in general is highly drugable, identification of kinases essential for maintaining chemoresistance could prove therapeutically useful. Hence we compared cellular kinase activity in chemotherapy resistant MCF7Res cells to chemotherapy-sensitive MCF cells using a peptide array approach that provides an atlas of cellular kinase activities and consequently, predominant pathways can be identified...
December 29, 2017: Oncotarget
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