JAK Inhibitors for Treatment of Psoriasis: Focus on Selective TYK2 Inhibitors
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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 -
Erb‑B2 Receptor Tyrosine Kinase 2 Is Negatively Regulated by the P53‑Responsive Microrna‑3184‑5P in Cervical Cancer Cells
ONCOLOGY REPORTS 45: 95-106, 2021 Erb‑B2 Receptor Tyrosine Kinase 2 is negatively regulated by the p53‑responsive microRNA‑3184‑5p in cervical cancer cells HONGLI LIU1, YUZHI LI1, JING ZHANG1, NAN WU2, FEI LIU2, LIHUA WANG1, YUAN ZHANG1, JING LIU1, XUAN ZHANG3, SUYANG GUO1 and HONGTAO WANG4 Departments of 1Gynecological Oncology and 2Respiration and Anhui Clinical and Preclinical Key Laboratory of Respiratory Disease, First Affiliated Hospital of Bengbu Medical College; Departments of3 Gynecological Oncology and 4Immunology and Anhui Key Laboratory of Infection and Immunity, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China Received November 30, 2019; Accepted October 2, 2020 DOI: 10.3892/or.2020.7862 Abstract. The oncogenic role of Erb-B2 Receptor Tyrosine Introduction Kinase 2 (ERBB2) has been identified in several types of cancer, but less is known on its function and mechanism of Among women, cervical cancer is ranked 4th in global action in cervical cancer cells. The present study employed cancer-associated deaths (1), with over half a million deaths a multipronged approach to investigate the role of ERBB2 in in 2012 (2). Cervical cancer can be broadly categorized into cervical cancer. ERBB2 and microRNA (miR)-3184-5p expres- squamous cell carcinoma, which constitutes the majority of sion was assessed in patient-derived cervical cancer biopsy cases (70-80%) or adenocarcinoma, which comprises 10-15% tissues, revealing that higher levels of ERBB2 and lower levels of cases (3). Cervical cancer is frequently caused by the of miR-3184-5p were associated with clinicopathological indi- oncovirus human papillomavirus (HPV), mainly by types cators of cervical cancer progression. -
Pharmacy Prior Authorization Criteria
Central California Alliance for Health Pharmacy Prior Authorization Criteria March 2020 Notice of Nondiscrimination and Accessibility Discrimination is Against the Law Central California Alliance for Health (the Alliance) complies with Federal civil rights and nondiscrimination laws to make sure all members have access to its programs and services. This means that the Alliance does not exclude or treat members differently because of race, color, national origin, age, disability, or sex. The Alliance provides services, at no cost, to help members communicate with us. • Members with a disability can ask for: ○ A trained sign language interpreter, and ○ Written information in large print, audio, easy to use electronic formats and other formats. • Members whose primary language is not English can ask for: ○ A trained language interpreter, and ○ Information written in a language they can understand. If you need these services, contact the Alliance Member Services Department at 1-800-700-3874 or if you believe that the Alliance did not provide these services or treated you differently because of race, color, national origin, age, disability, or sex, you can file a grievance in any of these ways: Phone: 1-800-700-3874 ext. 5816 Website: https://www.ccah-alliance.org/Complaints.html Fax: 1-831-430-5579 Email: [email protected] Mail: Grievance Department 1600 Green Hills Road, Suite 101 Scotts Valley, CA 95066 If you need help filing a grievance, our Member Service Representatives and Grievance Coordinators can help you. Contact the Alliance Member Services Department at 1-800-700-3874 or Grievance Department at 1-800-700-3874, ext. -
WO 2018/223101 Al 06 December 2018 (06.12.2018) W !P O PCT
(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 2018/223101 Al 06 December 2018 (06.12.2018) W !P O PCT (51) International Patent Classification: (71) Applicant: JUNO THERAPEUTICS, INC. [US/US]; 400 A 61K 35/1 7 (20 15.0 1) A 61P 35/00 (2006 .0 1) Dexter Ave. N., Suite 1200, Seattle, WA 98109 (US). (21) International Application Number: (72) Inventor: ALBERTSON, Tina; 400 Dexter Ave. N., Suite PCT/US2018/035755 1200, Seattle, WA 98109 (US). (22) International Filing Date: (74) Agent: AHN, Sejin et al; Morrison & Foerster LLP, 1253 1 0 1 June 2018 (01 .06.2018) High Bluff Drive, Suite 100, San Diego, CA 92130-2040 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, 62/5 14,774 02 June 2017 (02.06.2017) US CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, 62/5 15,530 05 June 2017 (05.06.2017) US DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, 62/521,366 16 June 2017 (16.06.2017) u s HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 62/527,000 29 June 2017 (29.06.2017) u s KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 62/549,938 24 August 2017 (24.08.2017) u s MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 62/580,425 0 1 November 2017 (01 .11.2017) u s OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 62/593,871 0 1 December 2017 (01 .12.2017) u s SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 62/596,764 08 December 2017 (08.12.2017) u s TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. -
Ruxolitinib for Symptom Control in Patients with Chronic Lymphocytic Leukaemia: a Single- Group, Phase 2 Trial
UC Irvine UC Irvine Previously Published Works Title Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single- group, phase 2 trial. Permalink https://escholarship.org/uc/item/1180x27h Journal The Lancet. Haematology, 4(2) ISSN 2352-3026 Authors Jain, Preetesh Keating, Michael Renner, Sarah et al. Publication Date 2017-02-01 DOI 10.1016/s2352-3026(16)30194-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Lancet Haematol Manuscript Author . Author Manuscript Author manuscript; available in PMC 2018 February 01. Published in final edited form as: Lancet Haematol. 2017 February ; 4(2): e67–e74. doi:10.1016/S2352-3026(16)30194-6. Ruxolitinib for symptom control in patients with Chronic Lymphocytic leukemia: A Phase II Trial Preetesh Jain, M.D.,PhD1, Michael Keating, M.D.1,*, Sarah Renner, RN1, Charles Cleeland, PhD2,*, Huang Xuelin, PhD3,*, Graciela Nogueras Gonzalez, M.P.H3, David Harris, PhD1, Ping Li, PhD1, Zhiming Liu, PhD1, Ivo Veletic, PhD1, Uri Rozovski, M.D.1, Nitin Jain, M.D.1, Phillip Thompson, M.D.1, Prithviraj Bose, M.D.1, Courtney DiNardo, M.D.1, Alessandra Ferrajoli, M.D.1,*, Susan O’Brien, M.D.1,*, Jan Burger, M.D.1, William Wierda, M.D.1,*, Srdan Verstovsek, M.D.1,*, Hagop Kantarjian, M.D.1,*, and Zeev Estrov, M.D.1,* 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 2Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas Summary Background—Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. -
Accepted Manuscript
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2020 JAK efficacy in Crohn’s disease Rogler, Gerhard Abstract: Inhibition of Janus kinases in Crohn’s disease (CD) patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor showed efficacy in ulcerative colitis (UC) and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in patients suffering from CD were disappointing and the primary endpoint of clinical remission could notbemet in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, inCD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subse- quently phase III programs in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are tested in clinical programs. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity (Tyk2 inhibitors). In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD. DOI: https://doi.org/10.1093/ecco-jcc/jjz186 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-178518 Journal Article Accepted Version Originally published at: Rogler, Gerhard (2020). JAK efficacy in Crohn’s disease. -
Stem Cell/Wnt
Inhibitors, Agonists, Screening Libraries www.MedChemExpress.com Stem Cell/Wnt Stem cells are required for continuous tissue maintenance within diverse organs, stem cell activity is often externally dictated by the microenvironment (the niche) so that stem cell output is precisely shaped to meet homeostatic needs or regenerative demands. Several key signaling pathways have been shown to play essential roles in this regulatory capacity. Specifically, the JAK/STAT, Hedgehog, Wnt, Notch, Smad, PI3K/phosphatase and tensin homolog, and NK-κB signaling pathways have all been shown experimentally to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. Recent studies mainly focus on cancer stem cell, induced pluripotent stem cell, neural stem cell and maintenance of embryonic stem cell pluripotency. Cancer stem cells (CSCs) have been believed to be responsible for tumor initiation, growth, and recurrence. Numerous agents have been developed to specifically target CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2, and c-Myc and transcription of GLI. Induced pluripotent stem cells (iPSCs) have the capacity to differentiate into various types of cells, and a self-renewing resource, and scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated. References: [1] Clevers H, et al. Science. 2014 Oct 3;346(6205):1248012. [2] Matsui WH. Medicine (Baltimore). -
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. -
Clinical Review Report for Upadacitinib (Rinvoq) 2
CADTH COMMON DRUG REVIEW Clinical Review Report Upadacitinib (Rinvoq) (AbbVie) Indication: For the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Service Line: CADTH Common Drug Review Version: Final (with redactions) Publication Date: March 2020 Report Length: 116 Pages Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionprofessionals,als, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patientspatients and others may access this documendocument,t, the document is made available for informational purposes only and no rrepresentationsepresentations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be usedused as a substitute for professional medical advice or as a substitusubstitutete for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processesprocesses,, or servicservices.es. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-datedate as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any thithirdrd-party materials used in preparing this document. -
Switching Between Janus Kinase Inhibitor Upadacitinib and Adalimumab Following Insufficient Response: Efficacy and Safety In
Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-218412 on 4 November 2020. Downloaded from Rheumatoid arthritis CLINICAL SCIENCE Switching between Janus kinase inhibitor upadacitinib and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid arthritis Roy M Fleischmann ,1 Ricardo Blanco ,2 Stephen Hall,3 Glen T D Thomson,4 Filip E Van den Bosch,5,6 Cristiano Zerbini,7 Louis Bessette,8,9 Jeffrey Enejosa,10 Yihan Li,10 Yanna Song,10 Ryan DeMasi,10 In- Ho Song10 Handling editor Josef S ABSTRACT Key messages Smolen Objectives To evaluate efficacy and safety of immediate switch from upadacitinib to adalimumab, or ► Additional material is What is already known about this subject? published online only. To view, vice versa, in patients with rheumatoid arthritis with non- ► In patients with rheumatoid arthritis, a treat- please visit the journal online response or incomplete- response to the initial therapy. to- target strategy is recommended, in which (http:// dx. doi. org/ 10. 1136/ Methods SELECT-COMP ARE randomised patients to therapy is optimised every 3–6 months until annrheumdis- 2020- 218412). upadacitinib 15 mg once daily (n=651), placebo (n=651) remission, or low disease activity, is achieved. or adalimumab 40 mg every other week (n=327). A For numbered affiliations see Recent treatment recommendations suggest the treat-to- target study design was implemented, with end of article. addition of a biological or targeted- synthetic blinded rescue occurring prior to week 26 for patients disease- modifying antirheumatic drug in Correspondence to who did not achieve at least 20% improvement in both patients who do not achieve treatment goals, Dr Roy M Fleischmann, The tender and swollen joint counts (’non-responders’) and and switches between mechanisms of action University of Texas at week 26 based on Clinical Disease Activity Index Southwestern Medical Center, occur commonly in clinical practice. -
Biomarker Testing in Non- Small Cell Lung Cancer (NSCLC)
The biopharma business of Merck KGaA, Darmstadt, Germany operates as EMD Serono in the U.S. and Canada. Biomarker testing in non- small cell lung cancer (NSCLC) Copyright © 2020 EMD Serono, Inc. All rights reserved. US/TEP/1119/0018(1) Lung cancer in the US: Incidence, mortality, and survival Lung cancer is the second most common cancer diagnosed annually and the leading cause of mortality in the US.2 228,820 20.5% 57% Estimated newly 5-year Advanced or 1 survival rate1 metastatic at diagnosed cases in 2020 diagnosis1 5.8% 5-year relative 80-85% 2 135,720 survival with NSCLC distant disease1 Estimated deaths in 20201 2 NSCLC, non-small cell lung cancer; US, United States. 1. National Institutes of Health (NIH), National Cancer Institute. Cancer Stat Facts: Lung and Bronchus Cancer website. www.seer.cancer.gov/statfacts/html/lungb.html. Accessed May 20, 2020. 2. American Cancer Society. What is Lung Cancer? website. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed May 20, 2020. NSCLC is both histologically and genetically diverse 1-3 NSCLC distribution by histology Prevalence of genetic alterations in NSCLC4 PTEN 10% DDR2 3% OTHER 25% PIK3CA 12% LARGE CELL CARCINOMA 10% FGFR1 20% SQUAMOUS CELL CARCINOMA 25% Oncogenic drivers in adenocarcinoma Other or ADENOCARCINOMA HER2 1.9% 40% KRAS 25.5% wild type RET 0.7% 55% NTRK1 1.7% ROS1 1.7% Oncogenic drivers in 0% 20% 40% 60% RIT1 2.2% squamous cell carcinoma Adenocarcinoma DDR2 2.9% Squamous cell carcinoma NRG1 3.2% Large cell carcinoma