scaffolds evalua...Figure 7.6 Structural differences contributing to selectivity for PI3Kα over...Figure 7.7 In vitro characterization of taselisib.Figure 7.8 Dose–response curves of fitted MCF7‐neo/HER2 tumor volumes in res...Figure 7.9 Simulations of plasma concentration–time profiles of taselisib in...7 Chapter 8Figure 8.1 Encoding strategies: (a) DNA‐templated synthesis; (b) Vipergen Yo...Figure 8.2 Split‐and‐pool synthesis of DELs.Figure 8.3 Structure of DNA for DEL synthesis.Figure 8.4 Summary of the ELT selection process.Figure 8.5 (a) Synthesis of DELs A and B. (b) Synthesis of on‐DNA AUDA tool ...Figure 8.6 qPCR analysis measuring the yield of DEL‐A and on‐DNA AUDA in the...Figure 8.7 (a) DELs A and B. (b) Selection output with DEL‐B under different...Figure 8.8 Structure of ELT‐delivered asset 22 and GSK2256294, a candidate m...
8 Chapter 9Figure 9.1 Number of total unique receptor complexes per year (www.gpcrdb.or...Figure 9.2 GPCR binding site computational analysis. Comparison of two Famil...Figure 9.3 CRF1R structures. In the left panels, the CRF1R inactive conforma...Figure 9.4 Importance of residence time for CRF1R negative allosteric modula...Figure 9.5 Crystal structure of the GCGR bound to MK‐0893 (PDB ID 5EE7) [45]...Figure 9.6 Molecular structures of agonist positive allosteric modulators co...Figure 9.7 Example of known GLP1R antagonist from Vanderbilt University [58,...Figure 9.8 Molecular structure of HTL26119.Figure 9.9 Protocol used to generate the VS databases of commercially availa...Figure 9.10 VS hits and initial lead. (a) The two‐dimensional structures of ...Figure 9.11 (a) (side view) and (b) (extracellular view) include a compariso...Figure 9.12 SAR highlights that resulted in the discovery of HTL26119. In th...
9 Chapter 10Figure 10.1 Profiles of compounds 1 and 2.Figure 10.2 In vitro autoradiography with [3H]2 in mouse brain slices. (a)To...Figure 10.3 Profile of compound 5 and SAR on the tail piece and northeastern...Figure 10.4 Comparison of time–activity curves and brain images among [11C]2 Figure 10.5 Chemical structure and in vitro properties of compound 10. Figure 10.6 Modifications on the core.Figure 10.7 Time–activity curves for [11C]10 and [11C]22 in monkey brain.Figure 10.8 Time–activity curves for [11C]10 and [18F]23 in monkey brain.Figure 10.9 (a) Snapshot of [11C]22 brain imaging in WT and P‐gp KO rat. (b)...Figure 10.10 (a) Scatter plot of PSA vs. rat P‐gp efflux ratio. Vertical lin...Figure 10.11 Scatter plot of rat PPB vs. HPLC Log D. Vertical line: X = 3.00...Figure 10.12 (a) Structures and in vitro properties of 31, 32, and 33. (b) P...Figure 10.13 (a) Summed image (0–90 minutes) of [11C]10 in rhesus monkey hig...Figure 10.14 PET image of [11C]MK‐6884 distribution in the brain of a health...
10 Chapter 11Figure 11.1 Regulation of protein drug targets by different approaches.Figure 11.2 Ubiquitination.Figure 11.3 Degradation of polyubiquitinated protein by the proteasome.Figure 11.4 The mechanism of action of PROTACs.Figure 11.5 PROTAC‐1.Figure 11.6 Peptide based PROTACs targeting AR (a) and ER (b).Figure 11.7 HIF‐1α based PROTAC.Figure 11.8 The first small molecule based PROTAC.Figure 11.9 VHL ligand based PROTAC (a) and CRBN ligand based PROTAC (b).Figure 11.10 (a) Structure of TrkA PhosphoProtac. (b) PhosphoPROTAC ErbB2PPP...Figure 11.11 Small molecule E3 ligase ligands.Figure 11.12 The crystal structure of the Brd4BD2‐MZ1‐VHL‐elonginC‐elonginB ...Figure 11.13 Hook effect. (a) PROTAC‐mediated ternary complex formation and ...Figure 11.14 The first all small molecule based PROTAC and verification of p...Figure 11.15 AR PROTACs based on the AR antagonist RU59063 and adamantly typ...Figure 11.16 AR PROTAC ARCC‐4. (a) Structure of ARCC‐4. (b) Degradation curv...Figure 11.17 AR degrader SNIPER(AR)‐51.Figure 11.18 (a) Structure of ARD‐69. (b) Pharmacodynamics (PD) study of ARD...Figure 11.19 Androgen receptor targeting PROTAC ARD‐61. (a) Structure of ARD...Figure 11.20 (a) Western blot analysis of ARV‐110 in LNCaP cells showing pot...Figure 11.21 Bio‐orthogonal strategy using click chemistry to assemble the l...Figure 11.22 Bio‐orthogonal strategy to generate the ERK‐CLIPTAC (click‐form...Figure 11.23 BET targeting PHOTAC‐I‐3 [31].Figure 11.24 FKBP123 targeting PHOTAC‐II‐5.Figure 11.25 Antibody‐PROTAC conjugate.Figure 11.26 ARV‐110 showed dose proportional human PK. (a) AUC 0–24 of...Figure 11.27 Structure of ARV‐110.Figure 11.28 Human PK of ARV‐471. PO 30 mg, QD. ()Figure 11.29 Structure of ARV‐471.
11 Chapter 12Figure 12.1 Peptide science milestones. Macrocyclic peptides are highlighted...Figure 12.2 Structures of macrocyclic peptides insulin, oxytocin, somatostat...Figure 12.3 Structures of α‐melanocyte‐stimulating hormone (α‐MSH) and macro...Figure 12.4 Structures of macrocyclic peptides linaclotide, zilucoplan, a PC...Figure 12.5 Structure of macrocyclic peptide BCY12491 highlighting its CD137...Figure 12.6 Structures of macrocyclic peptides cyclosporin A, a XIAP‐BIR3 in...Figure 12.7 Structures of cell‐permeable macrocyclic peptide “prodrug” of CA...Figure 12.8 Structures of macrocyclic peptides ATSP‐7041 and dPMI‐d(1–5‐12) ...Figure 12.9 Multidisciplinary paradigm for macrocyclic peptide drug discover...
12 Chapter 13Figure 13.1 (a) Anthramycin (PBD monomer), (b) PBD core structure, and (c) i...Figure 13.2 (a) Structure of SJG‐136 binding with DNA. (b) Interstrand cross...Figure 13.3 The SAR of the PBDs: (a) monomers, (b) dimers, and (c) unsymmetr...Figure 13.4 Non‐site‐specific and site‐specific PBD‐ADCs conjugations.Figure 13.5 SG‐3199 (payload), SG‐3249 (linker‐payload), and SG‐3199 ADC.Scheme 13.1 Synthesis of SG‐3249. Reagents and conditions: (a) Alloc‐Cl, pyr...Figure 13.6 The structures of ADCT‐601 and its ADCs.Figure 13.7 SGD‐1882 payload, the payload‐linker SGD‐1910 (Talirine), and SG...Scheme 13.2 Synthesis of SG‐1882. Reagents and conditions: (a) Ac2O, pyridin...Scheme 13.3 Synthesis of IGN462 and IMGN779. Reagents and conditions: (a) 3‐...Scheme 13.4 Synthesis of IGN549, IMGN632, and TAK164. Reagents and condition...Figure 13.8 IMGN779 and its ADCs.Figure 13.9 IMGN632 and its ADCs.Figure 13.10 TK‐164 and its ADCs.Figure 13.11 Pyrridinobenzodiazepines.Figure 13.12 D212 and its ADCs.Figure 13.13 PBD‐duocarmycin dimer ADCs.Figure 13.14 PBD dimer with thio‐oxophosphane ADC.Figure 13.15 Oxazolidine pro‐PBD as latent payload [91].Figure 13.16 The model release study of oxazolidine pro‐PBD.Figure 13.17 Pro‐PBD SMDC (EC2629).Scheme 13.5 Synthesis of EC2629. Reagents and conditions: (a) ethanolamine, ...Figure 13.18 Oxime ether pro‐PBD as latent payload.Scheme 13.6 Synthesis of SMDC2. Reagents and conditions: (a) 6‐1, iPr2 Figure 13.19 Increasing the therapeutic index from (a) by cytotoxic drugs to...Figure 13.20 An exposure‐centric approach to TI determination in humans [108...Figure 13.21 β‐Glucoronide prodrug of PBD dimer ADCs (SG3600 ADC).
13 Chapter 14Figure 14.1 Two‐dimensional isobologram based on Loewe's additivity model sh...Figure 14.2 Three‐dimensional isobologram illustrating drug combination data...Figure 14.3 Synthetic lethality of PARP inhibitor in BRCA‐deficient cells.Figure 14.4 Structures of representative PARP inhibitors.Figure 14.5 Representative drugs from different generations of cephalosporin...Figure 14.6 The mechanism of class A, B, C, and D β‐lactamase catalyzed hydr...Figure 14.7 Structures of β‐lactamase inhibitors.Figure 14.8 The mechanism of inactivation of β‐lactamases by avibactam.
14 Chapter 15Figure 15.1 Graphic illustration of bench and bedside in connection with tra...Figure 15.2 Optimal bidirectional interactions between the four phases of tr...Figure 15.3 Cartoon of the major components of the COVID virus.Figure 15.4 The estimated best timeframes for the application of the PCR, an...Figure 15.5 Life cycle of SARS‐CoV‐2 in host cells.Figure 15.6 Structures of remdesivir, parent of remdesivir GS‐441524, interm...Figure 15.7 Schematic illustration of typical vaccine development stages and...Figure 15.8 Chemical structure of dexamethasone.
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