1.17 Kinase inhibitors developed by Sugen.2 Chapter 2Figure 2.1 Degrader‐mediated targeted protein degradation (illustrated with ...Figure 2.2 Historical development of degraders since their first report in 2...Figure 2.3 Structures of IMiDs binding to E3 ligase CRBN (for more details o...Figure 2.4 Structure of VHL‐1, an optimized binder to E3 ligase VHL.Figure 2.5 Increasing number of publications on degraders.Figure 2.6 Structures of ligands that can be used to design degraders to rec...Figure 2.7 General strategy using the Huisgen reaction for parallel synthesi...Figure 2.8 The (un)druggable genome and number of potential targets.Figure 2.9 Oversaturation of the system with degrader molecules leads to the...Figure 2.10 Crystal structures of natural product molecular glues: Calcineur...Figure 2.11 A comparison of binary versus ternary complex formation approach...Figure 2.12 MoA of (a) Thalidomide, (b) Pomalidomide and (c) Lenalidomide: C...Figure 2.13 Molecular glue‐like degraders of the next generation: (a) CC‐885...Figure 2.14 Examples of monovalent degraders, degradation tails if identifie...
3 Chapter 3Figure 3.1 Human proglucagon (as encoded on complementary DNA). GRPP, glicen...Figure 3.2 Peptide sequence of GLP‐1 (1‐37), GLP‐1 (7‐37), GLP‐1 (7‐36)‐amid...Figure 3.3 (a) Cryo EM structure of GLP‐1R in complex with GLP‐1 and the sig...Figure 3.4 Timeline for GLP‐1 discovery and compounds approved by the Americ...Figure 3.5 The primary structure of human GLP‐1 and Ex4.Figure 3.6 The primary structure of lixisenatide.Figure 3.7 Schematic representation of the structure of efpeglenatide [30]....Figure 3.8 Schematic representation of pegylated loxenatide: mPEG, methoxy p...Figure 3.9 The structure of liraglutide.Figure 3.10 The structure of semaglutide.Figure 3.11 The primary structure of taspoglutide.Figure 3.12 Schematic representation of albiglutide.Figure 3.13 Schematic diagram of dulaglutide. The GLP‐1 analog, linker regio...Figure 3.14 Sequence of GLP‐1, Ex4, glucagon, oxyntomodulin, GIP, NNC0090‐27...Figure 3.15 Lead structure of 11‐mer GLP‐1R agonists from Bristol‐Myers Squi...
4 Chapter 4Figure 4.1 Schematic representation of the mechanism of action of SGLT2 inhi...Figure 4.2 Structure of the marketed gliflozins or candidates in phase III c...Figure 4.3 Structure of the dual inhibitors phlorizin and licogliflozin, and...Scheme 4.1 The first synthesis of dapagliflozin developed by Washburn and co...Scheme 4.2 Synthesis of dapagliflozin (1) developed by Gou and coworkers [19...Scheme 4.3 Synthesis of dapagliflozin developed by Walczak and coworkers [20...Scheme 4.4 Synthetic route of dapagliflozin reported by Yu and coworkers [22...Scheme 4.5 Synthetic approach of sotagliflozin (2) developed by Goodwin et a...Scheme 4.6 Synthetic pathway to sotagliflozin (2) developed by Li and cowork...Scheme 4.7 Synthesis of empagliflozin (3) following the synthetic pathway re...Scheme 4.8 Synthesis of benzyl‐protected empagliflozin 45 by reaction of iod...Scheme 4.9 Synthesis of empagliflozin analogue 54 [28].Scheme 4.10 Synthetic route of bexafloglizin (4) developed by Sun and cowork...Scheme 4.11 Synthesis of luseogliflozin (5) by Kakinuma et al. [32]. (a) Syn...Scheme 4.12 Tofogliflozin synthesis reported by Chugai Pharmaceuticals [34]....Scheme 4.13 Preparation of the tofogliflozin's aglycone [38].Scheme 4.14 Preparation of glycone 90 [38].Scheme 4.15 Synthesis of tofogliflozin (6) [38].Scheme 4.16 Synthesis of ertugliflozin (7) carried out by Triantakonstanti e...Scheme 4.17 Synthesis of ipragliflozin (8) by Zhou and coworkers [45]. Licen...Scheme 4.18 Canagliflozin (9) synthesis according to Nomura et al. [48].Scheme 4.19 Canagliflozin (9) synthesis according to Nakamura and coworkers ...Scheme 4.20 Patented synthesis by Optimus Drugs Pvt. Ltd of canagliflozin (9 Scheme 4.21 Improved process for the synthesis of canagliflozin (9) develope...Scheme 4.22 Total synthesis of remogliflozin etabonate (10) by Kobayashi et ...Figure 4.4 Benefits versus risks of treatment with SGLT2 inhibitors.
5 Chapter 5Figure 5.1 T cell receptor and costimulatory activation or inhibition of T c...Figure 5.2 A comparison of the basic structure of engineered TCR and CAR con...Figure 5.3 CAR design and evolution. CAR molecules consist of an extracellul...Figure 5.4 Cellular kinetics of CART19 cells in leukemia patients. CART19 ex...Figure 5.5 Vein‐to‐vein workflow for the clinical manufacture of lentiviral ...Figure 5.6 Potential mechanisms of CAR T cell therapy in cancer. Cancer cell...
6 Chapter 6Figure 6.1 Structures of selected small‐molecule CGRP‐RA. (a) Telcagepant, (...Figure 6.2 Comparison of the placebo subtracted headache improvement at two ...Figure 6.3 Efficacy at early time points in the phase 2 chronic migraine tri...
7 Chapter 7Figure 7.1 (a) FVIIIa consists of the A1 subunit, the A2 subunit, and the li...Figure 7.2 Flow of process to identify the lead bispecific antibody (BS15). ...Figure 7.3 Multidimensional optimization flow to generate the bispecific ant...Figure 7.4 Schematic illustration of the emicizumab molecule. CDR, complemen...
8 Chapter 8Figure 8.1 Generation of R(−)‐2‐hydroxyglutarate by mIDH1.Figure 8.2 Structural Analysis of WT vs mIDH1 Proteins. Left panels show Wi...Figure 8.3 Inhibition of the mIDH1 R132H enzyme reaction via a diaphorase/re...Figure 8.4 HTS Hit 1 and retrosynthetic analysis of the 2,N‐diphenyl glycine...Figure 8.5 Key structural elements accounting for the enzymatic activity of ...Scheme 8.1 (a) Synthesis of derivatives of 2,N‐diphenyl glycine via the Ugi ...Figure 8.6 Tumor 2‐HG inhibition following one (a) and three BID doses (b) o...Figure 8.7 Tumor 2‐HG concentration following single QD dose of AGI‐14100 in...Scheme 8.2 Synthesis of AG‐120 via the Ugi reaction ([20]; supporting inform...Figure 8.8 Tumor 2‐HG concentration and AG‐120 plasma concentration fo...Figure 8.9 Ex vivo treatment with AG‐120 reduces 2HG in primary patien...Figure 8.10 Ex vivo treatment with AG‐120 increases differentiation ma...Figure 8.11 “Swim plot” showing each patient and treatment outcome of the be...
9 Chapter 9Figure 9.1 A simplified model of the cell cycle showing cyclin‐CDK complexes...Figure 9.2 The CDK4/6 pathway and oncogenic mutations.Figure 9.3 Structure‐based optimization of a fragment hit.Figure 9.4 Evolution of a fragment‐based series.Figure 9.5 Optimization of an existing kinase asset leading to ribociclib.Figure 9.6 Crystal structure of ribociclib bound to cyclin D1‐CDK4: ribocicl...Figure 9.7 Ribociclib arrests the cell cycle exclusively in G1: JeKo‐1 mantl...Figure 9.8 Ribociclib given orally once daily causes dose‐dependent tumor re...Figure 9.9 Activity of ribociclib in combination with the aromatase inhibito...
Guide
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