Janus Kinase Inhibitors and Fields of Usage
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Stanford Chem-H Presentation (PDF)
KiNativ® In situ kinase profiling Stanford University ChEM-H confidential @KiNativPlatform Principle of the KiNativ platform • ATP (or ADP) acyl phosphate binds to, and covalently modifies Lysine residues in the active site • Thus, ATP acyl phosphate with a desthiobiotin tag can be used capture and quantitate kinases in a complex lysate Acyl phosphate Desthiobiotin tag ATP 2 ATP acyl phosphate probe covalently modifies kinase in the active site Lysine 2 Lysine 1 3 ATP acyl phosphate probe covalently modifies kinase in the active site Lysine 2 Lysine 1 4 Samples trypsinized, probe-labeled peptides captured with streptavidin, and analyzed by targeted LC-MS2 Identification Quantitation Explicit determination of peptide Integration of signal from MS2 sequence and probe modification site fragment ions from MS2 spectrum 5 Comprehensive Coverage of Protein and Lipid Kinases Protein kinases Atypical kinases Green: Kinases detected on KiNativ Red: Kinases not detected on KiNativ ~80% of known protein and atypical kinases identified on the platform http://www.kinativ.com/coverage/protein-lipid.html 6 Profiling compound(s) on the KiNativ platform Control sample – add probe Sample: Lysate derived from any cell line or tissue from ANY species Treated sample – add inhibitor followed by probe Inhibited kinase Green: Kinases Blue: Probe Gray: Non-kinases Red: Inhibitor 7 Profiling compound(s) on the KiNativ platform Control sample – add probe MS signalMS Sample: Lysate derived from any cell line or tissue from ANY species Treated sample – add inhibitor -
Download Product Insert (PDF)
PRODUCT INFORMATION Pacritinib Item No. 16709 CAS Registry No.: 937272-79-2 Formal Name: 11-[2-(1-pyrrolidinyl)ethoxy]-14,19-dioxa- 5,7,27-triazatetracyclo[19.3.1.12,6.18,12] O heptacosa-1(25),2,4,6(27),8,10,12(26), 16E,21,23-decaene Synonym: SB1518 N N H MF: C28H32N4O3 FW: 472.6 N Purity: ≥98% O Stability: ≥2 years at -20°C Supplied as: A crystalline solid N O UV/Vis.: λmax: 285 nm Laboratory Procedures For long term storage, we suggest that pacritinib be stored as supplied at -20°C. It should be stable for at least two years. Pacritinib is supplied as a crystalline solid. A stock solution may be made by dissolving the pacritinib in the solvent of choice. Pacritinib is soluble in the organic solvent DMSO, which should be purged with an inert gas, at a concentration of approximately 0.5 mg/ml (slightly warmed). Pacritinib is sparingly soluble in aqueous solutions. To enhance aqueous solubility, dilute the organic solvent solution into aqueous buffers or isotonic saline. If performing biological experiments, ensure the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. We do not recommend storing the aqueous solution for more than one day. Description FMS-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) are tyrosine kinases that mediate cytokine signaling and are frequently mutated in cancers, particularly acute myeloid leukemia.1,2 Pacritinib is an 1 inhibitor of both FLT3 and JAK2 (IC50s = 22 and 23 nM, respectively). -
Rheumatology and CTD
Section 16 Section Editor: G Narsimulu Rheumatology and CTD 206. Refractory Rheumatoid Arthritis 214. Treatment of SLE beyond Steroids Rohini Handa Rathindra Nath Sarkar, Rudrajit Paul 207. Difficulties in Rheumatoid Arthritis 215. Gout Is the Only Enemy That I Do Not Rajan Kumar Wish to Have at My Feet Anjana Pandey, Ajay Maurya, PK Maheshwari 208. Monoarthritis—A Clinical Dilemma to Internists Arup Kumar Kundu, Abhishek Kundu 216. Liver Dysfunction and NAFLD in RA: 209. Oral Targeted Treatments in RA—Update 2021 Is MTX Really a Culprit? Ramakrishna Rao Uppuluri, Sripurna Deepti Challa Kartik Nikhil Balankhe, Rishabh Ramu Nayak, Pulin Kumar Gupta 210. Biosimilars: Bane or Boon for India 217. Sexual Dysfunction in Rheumatic Diseases Durga Prasanna Misra, Pallavi Patro, Vikas Agarwal Vinod Ravindran 211. An Approach to Vasculitis 218. Interpretation of Common Investigations Packiamary Jerome in Rheumatology 212. How to Manage DMARDs Failure in RA? Renu Saigal, Amit Kansal, Vikram Raj Jain N Subramanian 213. IgG4-related Disease Harpreet Singh, Somdatta Giri, Anju Arya MU-206 (Sec-16).indd 1321 29-01-2021 15:25:29 MU-206 (Sec-16).indd 1322 29-01-2021 15:25:30 CHAPTER 206 Refractory Rheumatoid Arthritis Rohini Handa Abstract A sizeable number of patients with rheumatoid arthritis (RA) are unable to attain low disease activity or remission despite treatment. These difficult to treat (D2T) patients are labeled as refractory RA. The troika of D2T RA, as outlined by the European League against Rheumatism, comprises of treatment failure history, presence of active/symptomatic disease, and clinical perception. The approach to refractory RA is evolving. -
JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: a Focus on the Present and an Outlook on the Future
biomolecules Review JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future 1, 2, , 3 1,4 Jacopo Angelini y , Rossella Talotta * y , Rossana Roncato , Giulia Fornasier , Giorgia Barbiero 1, Lisa Dal Cin 1, Serena Brancati 1 and Francesco Scaglione 5 1 Postgraduate School of Clinical Pharmacology and Toxicology, University of Milan, 20133 Milan, Italy; [email protected] (J.A.); [email protected] (G.F.); [email protected] (G.B.); [email protected] (L.D.C.); [email protected] (S.B.) 2 Department of Clinical and Experimental Medicine, Rheumatology Unit, AOU “Gaetano Martino”, University of Messina, 98100 Messina, Italy 3 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Pordenone, 33081 Aviano, Italy; [email protected] 4 Pharmacy Unit, IRCCS-Burlo Garofolo di Trieste, 34137 Trieste, Italy 5 Head of Clinical Pharmacology and Toxicology Unit, Grande Ospedale Metropolitano Niguarda, Department of Oncology and Onco-Hematology, Director of Postgraduate School of Clinical Pharmacology and Toxicology, University of Milan, 20162 Milan, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-090-2111; Fax: +39-090-293-5162 Co-first authors. y Received: 16 May 2020; Accepted: 1 July 2020; Published: 5 July 2020 Abstract: Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. -
Clinical Efficacy of New JAK Inhibitors Under Development. Just More of the Same?
RHEUMATOLOGY Rheumatology 2019;58:i27i33 doi:10.1093/rheumatology/key256 Clinical efficacy of new JAK inhibitors under development. Just more of the same? Rene Westhovens1 Abstract Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use. Key words: Janus kinase inhibitor, RA, filgotinib, upadacitinib, peficitinib, decernotinib Rheumatology key messages . Efficacy but also some adverse events of most new Janus kinase inhibitors are dose dependent. Target selectivity of new Janus kinase inhibitors is an interplay between selectivity, dosing, drugdrug interaction, pharmacokinetics and pharmacodynamics. These new Janus kinase inhibitors might alter treatment paradigms by a rapid dose-dependent action, eventually also in monotherapy. Introduction regarding functionality, quality of life and even aspects of participation in daily life. -
Tanibirumab (CUI C3490677) Add to Cart
5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor -
Pathological Mechanisms and Modern Pharmacologic Therapies
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by espace@Curtin Bone Research www.nature.com/boneres REVIEW ARTICLE OPEN Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies Qiang Guo1,2, Yuxiang Wang1, Dan Xu2,3, Johannes Nossent3,4, Nathan J. Pavlos2 and Jiake Xu2 Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that primarily affects the lining of the synovial joints and is associated with progressive disability, premature death, and socioeconomic burdens. A better understanding of how the pathological mechanisms drive the deterioration of RA progress in individuals is urgently required in order to develop therapies that will effectively treat patients at each stage of the disease progress. Here we dissect the etiology and pathology at specific stages: (i) triggering, (ii) maturation, (iii) targeting, and (iv) fulminant stage, concomitant with hyperplastic synovium, cartilage damage, bone erosion, and systemic consequences. Modern pharmacologic therapies (including conventional, biological, and novel potential small molecule disease-modifying anti-rheumatic drugs) remain the mainstay of RA treatment and there has been significant progress toward achieving disease remission without joint deformity. Despite this, a significant proportion of RA patients do not effectively respond to the current therapies and thus new drugs are urgently required. This review discusses recent advances of our understanding of RA pathogenesis, disease modifying drugs, and provides perspectives on next generation therapeutics for RA. Bone Research (2018) 6:15 ; https://doi.org/10.1038/s41413-018-0016-9 INTRODUCTION manifestations such as keratitis, pulmonary granulomas (rheuma- Rheumatoid arthritis (RA) is a chronic systemic autoimmune toid nodules), pericarditis/pleuritis, small vessel vasculitis, and disease that arises more frequently in females than males, being other non-specific extra-articular symptoms will develop. -
Cytokine Signaling in Tumor Progression
Immune Netw. 2017 Aug;17(4):214-227 https://doi.org/10.4110/in.2017.17.4.214 pISSN 1598-2629·eISSN 2092-6685 Review Article Cytokine Signaling in Tumor Progression Myungmi Lee, Inmoo Rhee* Department of Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea Received: Apr 13, 2017 ABSTRACT Revised: Jun 22, 2017 Accepted: Jun 25, 2017 Cytokines are molecules that play critical roles in the regulation of a wide range of normal *Correspondence to functions leading to cellular proliferation, differentiation and survival, as well as in Inmoo Rhee specialized cellular functions enabling host resistance to pathogens. Cytokines released Department of Bioscience and Biotechnology, in response to infection, inflammation or immunity can also inhibit cancer development Sejong University, 209 Neungdong-ro, and progression. The predominant intracellular signaling pathway triggered by cytokines Gwangjin-gu, Seoul 05006, Korea. is the JAK-signal transducer and activator of transcription (STAT) pathway. Knockout mice Tel: +82-2-6935-2432 E-mail: [email protected] and clinical human studies have provided evidence that JAK-STAT proteins regulate the immune system, and maintain immune tolerance and tumor surveillance. Moreover, aberrant Copyright © 2017. The Korean Association of activation of the JAK-STAT pathways plays an undeniable pathogenic role in several types Immunologists of human cancers. Thus, in combination, these observations indicate that the JAK-STAT This is an Open Access article distributed under the terms of the Creative Commons proteins are promising targets for cancer therapy in humans. The data supporting this view Attribution Non-Commercial License (https:// are reviewed herein. creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial Keywords: Cytokine; JAK-STAT; Cancer; Kinase inhibitor use, distribution, and reproduction in any medium, provided the original work is properly cited. -
Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis
REVIEW published: 09 July 2021 doi: 10.3389/fimmu.2021.686155 Promising Therapeutic Targets for Treatment of Rheumatoid Arthritis † † Jie Huang 1 , Xuekun Fu 1 , Xinxin Chen 1, Zheng Li 1, Yuhong Huang 1 and Chao Liang 1,2* 1 Department of Biology, Southern University of Science and Technology, Shenzhen, China, 2 Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China Rheumatoid arthritis (RA) is a systemic poly-articular chronic autoimmune joint disease that mainly damages the hands and feet, which affects 0.5% to 1.0% of the population worldwide. With the sustained development of disease-modifying antirheumatic drugs (DMARDs), significant success has been achieved for preventing and relieving disease activity in RA patients. Unfortunately, some patients still show limited response to DMARDs, which puts forward new requirements for special targets and novel therapies. Understanding the pathogenetic roles of the various molecules in RA could facilitate discovery of potential therapeutic targets and approaches. In this review, both Edited by: existing and emerging targets, including the proteins, small molecular metabolites, and Trine N. Jorgensen, epigenetic regulators related to RA, are discussed, with a focus on the mechanisms that Case Western Reserve University, result in inflammation and the development of new drugs for blocking the various United States modulators in RA. Reviewed by: Åsa Andersson, Keywords: rheumatoid arthritis, targets, proteins, small molecular metabolites, epigenetic regulators Halmstad University, Sweden Abdurrahman Tufan, Gazi University, Turkey *Correspondence: INTRODUCTION Chao Liang [email protected] Rheumatoid arthritis (RA) is classified as a systemic poly-articular chronic autoimmune joint † disease that primarily affects hands and feet. -
A Closer Look at JAK/STAT Signaling Pathway Emira Bousoik Chapman University
Chapman University Chapman University Digital Commons Pharmacy Faculty Articles and Research School of Pharmacy 7-31-2018 “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway Emira Bousoik Chapman University Hamidreza Montazeri Aliabadi Chapman University, [email protected] Follow this and additional works at: https://digitalcommons.chapman.edu/pharmacy_articles Part of the Amino Acids, Peptides, and Proteins Commons, Cancer Biology Commons, Cell Anatomy Commons, Cell Biology Commons, Enzymes and Coenzymes Commons, Oncology Commons, and the Other Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Bousoik E, Montazeri Aliabadi H. “Do we know jack” about JAK? A closer look at JAK/STAT signaling pathway. Front. Oncol. 2018;8:287. doi: 10.3389/fonc.2018.00287 This Article is brought to you for free and open access by the School of Pharmacy at Chapman University Digital Commons. It has been accepted for inclusion in Pharmacy Faculty Articles and Research by an authorized administrator of Chapman University Digital Commons. For more information, please contact [email protected]. “Do We Know Jack” About JAK? A Closer Look at JAK/STAT Signaling Pathway Comments This article was originally published in Frontiers in Oncology, volume 8, in 2018. DOI: 10.3389/ fonc.2018.00287 Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. Copyright The uthora s This article is available at Chapman University Digital Commons: https://digitalcommons.chapman.edu/pharmacy_articles/590 -
WO 2016/040858 Al 17 March 2016 (17.03.2016) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/040858 Al 17 March 2016 (17.03.2016) P O P C T (51) International Patent Classification: (72) Inventors: STRUM, Jay, Copeland; c/o Gl Therapeutics, A61K 31/519 (2006.01) Inc., 79 Tw Alexander Drive, Suite 105, Research Triangle Park, NC 27709 (US). BISI, John, Emerson; C/o Gl (21) International Application Number: Therapeutics, Inc., 79 Tw Alexander Drive, Suite 105, Re PCT/US20 15/049777 search Triangle Park, NC 27709 (US). ROBERTS, (22) International Filing Date: Patrick, Joseph; c/o G l Therapeutics, Inc., 79 Tw Alexan 11 September 2015 ( 11.09.201 5) der Drive, Suite 105, Research Triangle Park, NC 27709 (US). SORRENTINO, Jessica, Ann; C/o G l Therapeut (25) Filing Language: English ics, Inc., 79 TW Alexander Drive, Suite 105, Research Tri (26) Publication Language: English angle Park, NC 27709 (US). STORRIE-WHITE, Han¬ nah; c/o G l Therapeutics, Inc., 79 Tw Alexander Drive, (30) Priority Data: Suite 105, Research Triangle Park, NC 27709 (US). 62/050,043 12 September 2014 (12.09.2014) US (74) Agent: BELLOWS, Brent, R.; Knowles Intellectual Prop (71) Applicant: Gl THERAPEUTICS, INC. [US/US]; 79 TW erty Strategies, LLC, 400 Perimeter Center Terrace NE, Alexander Drive, Suite 105, Research Triangle Park, NC Suite 200, Atlanta, GA 30346 (US). 27709 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. -
Pacritinib Combined with Sirolimus and Low-Dose Tacrolimus for GVHD
Author Manuscript Published OnlineFirst on March 22, 2021; DOI: 10.1158/1078-0432.CCR-20-4725 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Pidala J et al GVHD prevention with combined JAK2/mTOR inhibition Pacritinib combined with sirolimus and low-dose tacrolimus for GVHD prevention after allogeneic hematopoietic cell transplantation: Preclinical and Phase I trial results Authors: Joseph Pidala1-3, Kelly Walton4, Hany Elmariah1,3, Jongphil Kim5, Asmita Mishra1,3, Nelli Bejanyan1,3, Taiga Nishihori1,3, Farhad Khimani1,3, Lia Perez1,3, Rawan G. Faramand1,3, Marco L. Davila1-3, Michael L. Nieder1,3, Elizabeth M. Sagatys6, Shernan G. Holtan4, Nicholas J. Lawrence7, Harshani R. Lawrence7, Bruce R. Blazar8, Claudio Anasetti1-3, Said M. Sebti9, Brian C. Betts4* Affiliations: 1Department of Blood and Marrow Transplantation – Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA, 2Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA, 3Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA, 4Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA, 5Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA, 6Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA, 7Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA, 8Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA, 9Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia USA. Running Title: GVHD prevention with combined JAK2/mTOR inhibition *Address correspondence to: Brian C. Betts, MD Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota Nils Hasselmo Hall, Room 2-108, 312 Church Street SE Minneapolis, MN 55455 [email protected] COI statement: B.C.B.