Oversight Committee Board Packet
Total Page：16
File Type：pdf, Size：1020Kb
Load more
Recommended publications
-
Corporate Governance
Strategic report Governance and remuneration Financial statements Investor information Corporate Governance In this section Chairman’s Governance statement 78 The Board 80 Corporate Executive Team 83 Board architecture 85 Board roles and responsibilities 86 Board activity and principal decisions 87 Our purpose, values and culture 90 The Board’s approach to engagement 91 Board performance 94 Board Committee information 96 Our Board Committee reports 97 Section 172 statement 108 Directors’ report 109 GSK Annual Report 2020 77 Chairman’s Governance statement In last year’s Governance statement, I explained that our primary Education and focus on Science objective for 2020 was to ensure there was clarity between the Given the critical importance of strengthening the pipeline, Board and management on GSK’s execution of strategy and its the Board has benefitted from devoting a higher proportion of operational priorities. We have aligned our long-term priorities its time in understanding the science behind our strategy and of Innovation, Performance and Trust powered by culture testing its application. It is important that the Board has a and agreed on the metrics to measure delivery against them. working understanding of the key strategic themes upon The Board’s annual cycle of meetings ensures that all major which our R&D strategy is based. These themes have been components of our strategy are reviewed over the course complemented by Board R&D science thematic deep dives. of the year. Our focus was on the fundamentals of our strategy: human The COVID-19 pandemic impacted and dominated all our genetics, the immune system and AI and ML, as well as to lives for the majority of 2020. -
On the Organization of a Drug Discovery Platform
DOI: 10.5772/intechopen.73170 ProvisionalChapter chapter 2 On the Organization of a Drug Discovery Platform Jean A. Boutin,A. Boutin, Olivier NosjeanOlivier Nosjean and Gilles FerryGilles Ferry Additional information is available at the end of the chapter http://dx.doi.org/10.5772/intechopen.73170 Abstract Some of the most exciting parts of work in the pharmaceutical industry are the steps lead- ing up to drug discovery. This process can be oversimplified by describing it as a screen- ing campaign involving the systematic testing of many compounds in a test relevant to a given pathology. This naïve description takes place without taking into consideration the numerous key steps that led up to the screening or the steps that might follow. The present chapter describes this whole process as it was conducted in our company dur- ing our early drug discovery activities. First, the purpose of the procedures is described and rationalized. Next follows a series of mostly published examples from our own work illustrating the various steps of the process from cloning to biophysics, including expression systems and membrane-bound protein purifications. We believe that what is described here presents an example of how pharmaceutical industry research can orga- nize its platform(s) when the goal is to find and qualify a new preclinical drug candidate using cutting-edge technologies and a lot of hard work. Keywords: drug discovery, validation, cloning & expression, biophysics, structural biology, organization 1. Introduction Drug discovery involves a suite of processes as part of a program aimed at finding drug thera- pies for diseases. These programs encompass many different scientific steps from validation of the target (or attempts to do so) and characterization of the hits until the selection of can- didates for medicinal chemistry programs. -
Predicting Strategies for Lead Optimization Via Learning to Rank
IPSJ Transactions on Bioinformatics Vol.11 41–47 (Dec. 2018) [DOI: 10.2197/ipsjtbio.11.41] Original Paper Predicting Strategies for Lead Optimization via Learning to Rank Nobuaki Yasuo1,2,a) Keisuke Watanabe1 Hideto Hara3 Kentaro Rikimaru3 Masakazu Sekijima1,4,b) Received: August 21, 2018, Accepted: September 18, 2018 Abstract: Lead optimization is an essential step in drug discovery in which the chemical structures of compounds are modified to improve characteristics such as binding affinity, target selectivity, physicochemical properties, and tox- icity. We present a concept for a computational compound optimization system that outputs optimized compounds from hit compounds by using previous lead optimization data from a pharmaceutical company. In this study, to predict the drug-likeness of compounds in the evaluation function of this system, we evaluated and compared the ability to correctly predict lead optimization strategies through learning to rank methods. Keywords: lead optimization, learning to rank, computer-aided drug design, machine learning computer-aided drug discovery (CADD), which has been utilized 1. Introduction since the 1960s, are also leading current drug discovery. The During drug discovery, enormous attempts are being made to methods of CADD can be combined with various biological data identify better drug candidates. Since the cost of drug discovery including genomic sequence, protein tertiary structure, and chem- has been drastically increased, recently the process of drug dis- ical structure, and can be utilized in various steps in drug discov- covery typically takes 12–14 years [1] and costs approximately ery: target identification, compound screening, and ADME (ab- 2.6 billion USD [2]. The process of drug discovery is sometimes sorption, distribution, metabolism, excretion, toxicity) properties likened to looking for a needle in a haystack; it is the process prediction [9], [10], [11]. -
Medicinal Chemistry for Drug Discovery | Charles River
Summary Medicinal chemistry is an integral part of bringing a drug through development. Our medicinal chemistry approach enables clients to benefit from efficient navigation of the early drug discovery process through to delivery of preclinical candidates. DISCOVERY Click to learn more Medicinal Chemistry for Drug Discovery Medicinal Chemistry A Proven Track Record in Drug Discovery Services: Our medicinal chemistry team has experience in progressing small molecule drug discovery programs across a broad range • Target identification of therapeutic areas and gene families. Our scientists are skilled in the design and synthesis of novel pharmacologically active - Capture Compound® mass compounds and understand the challenges facing modern drug discovery. Together, they are cited as inventors on over spectrometry (CCMS) 350 patents and have identified 80 preclinical candidates for client organizations across a variety of therapeutic areas. As • Hit-finding strategies project leaders, our chemists are fundamental in driving the program strategy and have consistently empowered our clients’ - Optimizing high-throughput success. A high proportion of candidates regularly progress to the clinic, and our first co-invented drug, Belinostat, received screening (HTS) hits marketing approval in 2015. As an organization, Charles River has worked on 85% of the therapies approved in 2018. • Hit-to-lead We have a deep understanding of the factors that drive medicinal chemistry design: structure-activity relationship (SAR), • Lead optimization biology, physical chemistry, drug metabolism and pharmacokinetics (DMPK), pharmacokinetic/pharmacodynamic (PK/PD) • Patent strategy modelling, and in vivo efficacy. Charles River scientists are skilled in structure-based and ligand-based design approaches • Preparation for IND filing utilizing our in-house computer-aided drug design (CADD) expertise. -
Notice of Meeting for the Eighteenth Annual General Meeting (AGM) of Glaxosmithkline Plc
GlaxoSmithKline plc Image HIV virus Notice of Annual General Meeting Thursday 3 May 2018 at 2.30pm This document is important and requires your immediate attention. If you are in any doubt as to what action you should take, you should consult your stockbroker, bank manager, solicitor, accountant or other independent professional adviser immediately. If you have sold or otherwise transferred all of your shares, please pass this document, together with the accompanying documents, to the purchaser or transferee, or to the person who arranged the sale or transfer so they can pass these documents to the person who now holds the shares. 2 29 March 2018 To the holders of the company’s Ordinary Shares and American Depositary Shares. Dear Shareholder, Annual General Meeting 2018 I am pleased to enclose the Notice of Meeting for the eighteenth Annual General Meeting (AGM) of GlaxoSmithKline plc. The AGM will be held on Thursday 3 May 2018 at 2.30pm at the QEII Centre, Broad Sanctuary, Westminster, London SW1P 3EE. If you will not be attending, you may appoint a proxy by completing and returning the enclosed proxy form. Alternatively, you may appoint a proxy electronically via www.shareview.co.uk, www.sharevote.co.uk or, if you hold your shares in CREST, via the CREST system. Notice of your appointment of a proxy should reach the company’s registrar, Equiniti, by 2.30pm on Tuesday 1 May 2018. If you hold your shares through a nominee service, please contact the nominee service provider regarding the process for appointing a proxy. Included in the business of the AGM are resolutions to receive and adopt the Directors’ Report and the Financial Statements for 2017, to approve the Annual report on remuneration for the year ended 31 December 2017 and to confirm the appointment of Deloitte LLP as the company’s auditors. -
DMPK) Studies Are Critical to Efficient Drug Discovery Programs and Successful Delivery of Candidate Molecules
Summary Discovery drug metabolism and pharmacokinetics (DMPK) studies are critical to efficient drug discovery programs and successful delivery of candidate molecules. DISCOVERY Drug Metabolism and Pharmacokinetics (DMPK) Click to learn more Supporting Discovery Research DMPK Services The identification and inclusion of appropriate DMPK studies is key to the success of discovery research by helping to de-risk • In vitro ADME candidate molecules and improve project productivity through more targeted chemical synthesis and progression of the right compounds. Charles River’s flexible and collaborativeDMPK team offers a variety of partnerships and pricing structures to suit • Physicochemical properties client needs. In addition to fee-for-service assays and expertise, we can embed our DMPK scientists within existing integrated • Metabolic stability chemistry programs as core team members of multidisciplinary project teams. We offer a wealth of experience in a range of • Drug-drug interactions therapeutic areas and biological targets and can help support strategy and implementation of appropriate screening cascades. • Distribution • Safety • High-throughput and automation Chemistry • Pharmacokinetics (PK) support • Bioanalysis and Biology pharmacokinetic support DMPK Questions for our chemists? Visit https://www.criver.com/ consult-pi-ds-questions-for-our- chemists EVERY STEP OF THE WAY www.criver.com In Vitro ADME As compound potency improves during hit-to-lead and lead optimization, in vitro ADME assays provide necessary data to establish insight into the key physiochemical properties and structural motifs that will provide the targeted candidate profile. Our in vitro ADME scientists have established a suite of assays that routinely support drug discovery programs, continue to work on the development and validation of new assays, and regularly monitor assay performance. -
Early Hit-To-Lead ADME Screening Bundle Bundled Screening Assays to Accelerate Candidate Selection in Drug Discovery
Fact Sheet Early Hit-to-Lead ADME Screening Bundle Bundled Screening Assays to Accelerate Candidate Selection in Drug Discovery In vitro ADME screening during the lead optimization stage of drug discovery positively impacts drug candidate selection with an enhanced probability of success in clinical trials. Since most new drug candidates fail during preclinical and clinical development, and the late stage of the drug development cycle can be a lengthy and costly process, any means of identifying drug candidates with optimized ADME and pharmacokinetics properties in the discovery stage will have a significant impact on the drug discovery process overall. Focused on Solutions to Address DMPK Issues and to Enable the Success of Our Clients Our scientists routinely conduct industry standard in vitro metabolism and DDI-based assays, including highly automated ADME in vitro screens. We can help drive your discovery phase structure activity relationship (SAR) by optimizing for ADME properties, in parallel to your receptor binding potency and selectivity, for more rapid identification of high quality drug candidates. Metabolic stability, risk assessment for inhibiting key Cytochrome P450 enzymes, and cell permeability are three main early hit-to-lead ADME screening assays that all new chemical entities (NCEs) are tested for in the industry in effort to optimize key ADME properties. In Vitro ADME Screening Services: Early Hit-to-Lead ADME Screening Bundle Intrinsic Clearance Assay in Liver Microsomes • Liver microsomes; species selectable • Incubation -
A New Ligand-Based Approach to Virtual Screening and Profiling of Large Chemical Libraries
A new ligand-based approach to virtual screening and profiling of large chemical libraries Elisabet Gregori Puigjané Memòria presentada per optar al grau de Doctor en Biologia per la Universitat Pompeu Fabra. Aquesta Tesi Doctoral ha estat realitzada sota la direcció del Dr. Jordi Mestres al Departament de Ciències Experimentals i de la Salut de la Universitat Pompeu Fabra Jordi Mestres Elisabet Gregori Puigjané Barcelona, Maig 2008 The research in this thesis has been carried out at the Chemogenomics Laboratory (CGL) within the Unitat de Recerca en Informàtica Biomèdica (GRIB) at the Parc de Recerca Biomèdica de Barcelona (PRBB). The research carried out in this thesis has been supported by Chemotargets S. L. Table of contents Acknowledgements ........................................................................................... 3 Abstract .............................................................................................................. 5 Objectives ........................................................................................................... 7 List of publications ............................................................................................ 9 Part I – INTRODUCTION .................................................................................. 11 Chapter I.1. Drug discovery ..................................................................... 13 I.1.1. Obtaining a drug candidate ....................................................... 14 I.1.1.1. Hit identification .......................................................... -
UNITED STATES SECURITIES and EXCHANGE COMMISSION Washington, D.C. 20549 SCHEDULE 13D INFORMATION to BE INCLUDED in STATEMENTS FI
UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 SCHEDULE 13D INFORMATION TO BE INCLUDED IN STATEMENTS FILED PURSUANT TO § 240.13d-1(a) AND AMENDMENTS THERETO FILED PURSUANT TO 240.13d-2(a) UNDER THE SECURITIES EXCHANGE ACT OF 1934 SPERO THERAPEUTICS, INC. (Name of Issuer) Common Stock, Par Value $0.001 (Title of Class of Securities) 84833T 10 3 (CUSIP Number) Victoria A. Whyte GlaxoSmithKline plc 980 Great West Road Brentford, Middlesex TW8 9GS England Telephone: +44 (0)208 047 5000 (Name, Address and Telephone Number of Person Authorized to Receive Notices and Communications) November 6, 2017 (Date of Event which Requires Filing of this Statement) If the filing person has previously filed a statement on Schedule 13G to report the acquisition that is the subject of this Schedule 13D, and is filing this schedule because of §§240.13d-1(e), 240.13d-1(f) or 240.13d-1(g), check the following box. ☐ Note: Schedules filed in paper format shall include a signed original and five copies of the schedule, including all exhibits. See §240.13d-7 for other parties to whom copies are to be sent. * The remainder of this cover page shall be filled out for a reporting person's initial filing on this form with respect to the subject class of securities, and for any subsequent amendment containing information which would alter disclosures provided in a prior cover page. The information required on the remainder of this cover page shall not be deemed to be "filed" for the purpose of Section 18 of the Securities Exchange Act of 1934 ("Act") or otherwise subject to the liabilities of that section of the Act but shall be subject to all other provisions of the Act. -
An Emerging Strategy for Rapid Target and Drug Discovery
R E V I E W S CHEMOGENOMICS: AN EMERGING STRATEGY FOR RAPID TARGET AND DRUG DISCOVERY Markus Bredel*‡ and Edgar Jacoby§ Chemogenomics is an emerging discipline that combines the latest tools of genomics and chemistry and applies them to target and drug discovery. Its strength lies in eliminating the bottleneck that currently occurs in target identification by measuring the broad, conditional effects of chemical libraries on whole biological systems or by screening large chemical libraries quickly and efficiently against selected targets. The hope is that chemogenomics will concurrently identify and validate therapeutic targets and detect drug candidates to rapidly and effectively generate new treatments for many human diseases. Over the past five decades, pharmacological compounds however, that owing to the emergence of various sub- TRANSCRIPTIONAL PROFILING The study of the transcriptome have been identified that collectively target the products specialties of chemogenomics (discussed in the next — the complete set of RNA of ~400–500 genes in the human body; however, only section) and the involvement of several disciplines, it is transcripts that are produced by ~120 of these genes have reached the market as the tar- currently almost impossible to give a simple and com- the genome at any one time — gets of drugs1,2. The Human Genome Project3,4 has mon definition for this research discipline (BOX 1). using high-throughput methods, such as microarray made available many potential new targets for drug In chemogenomics-based drug discovery, large col- analysis. intervention: several thousand of the approximately lections of chemical products are screened for the paral- 30,000–40,000 estimated human genes4 could be associ- lel identification of biological targets and biologically ated with disease and, similarly, several thousand active compounds. -
Hit-To-Lead (H2L) and Lead Optimization in Medicinal Chemistry
Hit-to-lead (H2L) and Lead Optimization in Medicinal Chemistry 1 This document provides an outline of a presentation and is incomplete without the accompanying oral commentary and discussion. Drug Discovery: Lead Optimization 2 Lecture Overview • Ligand-protein interactions. • Physico-chemical properties and drug design: attributes of a lead molecule. • Introduction to medicinal chemistry and lead optimization. • Best practices in medicinal chemistry. • Case-studies (Alzheimer’s disease): – Fragment-based approaches in discovery of beta- secretase inhibitors – Identification of a PDE9 clinical candidate 3 Lecture Overview • Ligand-protein interactions. • Physico-chemical properties and drug design: attributes of a lead molecule. • Introduction to medicinal chemistry and lead optimization. • Best practices in medicinal chemistry. • Case-studies (Alzheimer’s disease): – Fragment-based approaches in discovery of beta- secretase inhibitors – Identification of a PDE9 clinical candidate 4 Ligand-protein binding event SolutionSolução ComplexComplexo Gbind + Something to remember: 1.36 kcal/mol ~ 10-fold gain in affinity 2.72 kcal/mol ~ 100-fold 4.08 kcal/mol ~ 1000-fold 5 Some Factors Affecting Gbind Favor Binding Oppose Binding Entropy and enthalpy gain due to the “hydrophobic effect” – taking ligand out of Ligand desolvation enthalpy – loss of water eliminates the penalty associated with the interactions with the solvent. solvent cavity creation. Entropy and enthalpy gain due to the Binding pocket desolvation enthalpy – loss of “hydrophobic effect” for ordered waters bound interactions with the solvent. to protein moving to bulk solvent. Residual vibrational entropy in protein-ligand Translational and rotational entropy loss for complex. ligand and protein upon binding (loss of 3 translational and 3 rotational degrees of freedom). -
Hit Discovery and Hit-To-Lead Approaches Reviews
Drug Discovery Today Volume 11, Numbers 15/16 August 2006 REVIEWS POST SCREEN Hit discovery and hit-to-lead approaches Reviews Gyo¨ rgy M. Keseru˝ 1 and Gergely M. Makara2 1 CADD&HTS Unit, Gedeon Richter Ltd, 19-21 Gyo¨mro˝iu´t, Budapest, H-1103, Hungary 2 Merck Research Laboratories, Merck & Co, RY80Y-325, 126 E. Lincoln Ave, Rahway, New Jersey, 07065, USA Hit discovery technologies range from traditional high-throughput screening to affinity selection of large libraries, fragment-based techniques and computer-aided de novo design, many of which have been extensively reviewed. Development of quality leads using hit confirmation and hit-to-lead approaches present their own challenges, depending on the hit discovery method used to identify the initial hits. In this paper, we summarize common industry practices adopted to tackle hit-to-lead challenges and review how the advantages and drawbacks of different hit discovery techniques could affect the various issues hit-to-lead groups face. It has been shown that marketed drugs are very frequently highly All hit discovery approaches have – often orthogonal – short- similar to the leads from which they were derived [1]. Thus, both comings prompting the frequent use of multiple techniques for hit the quality and the quantity of lead classes available to medicinal confirmation (Table 1). Challenges facing traditional HTS tech- chemists are primary drivers for discovering best-in-class medi- nologies include high false-positive rates, the need for reporter cines. This makes lead generation a crucial step in the drug dis- assays and the limitation in throughput imposed by testing com- covery process.