Managing the drug discovery/development interface

Kennedy, Tony

doi:10.1016/s1359-6446(97)01099-4

Cited by 483 publications

(253 citation statements)

References 3 publications

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“…Furthermore, suitable DMPK features are essential to the selection of an effective clinical development candidate and its successful progression through clinical evaluation. Indeed, analysis of the major reasons for withdrawal of drugs from development in the 1980s revealed that 39% of failures could be attributed to inappropriate pharmacokinetics in man (14,15). Between 1991 and 2000, the rate of failure of drugs in clinical trials that could be attributed to poor DMPK/ bioavailability fell from f40% to just <10% (5).…”

Section: Dmpk In Drug Discoverymentioning

confidence: 99%

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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Pharmacokinetic evaluation is an essential component of drug discovery and should be conducted early in the process so that those compounds with the best chance of success are prioritized and progressed. However, pharmacokinetic analysis has become a serious bottleneck during the 'hit-to-lead' and lead optimization phases due to the availability of new targets and the large numbers of compounds resulting from advances in synthesis and screening technologies. Cassette dosing, which involves the simultaneous administration of several compounds to a single animal followed by rapid sample analysis by liquid chromatography/tandem mass spectrometry, was developed to increase the throughput of in vivo pharmacokinetic screening. Although cassette dosing is advantageous in terms of resources and throughput, there are possible complications associated with this approach, such as the potential for compound interactions. Following an overview of the cassette dosing literature, this article focuses on the application of the technique in anticancer drug discovery. Specific examples are discussed, including the evaluation of cassette dosing to assess pharmacokinetic properties in the development of cyclin-dependent kinase and heat shock protein 90 inhibitors. Subject to critical analysis and validation in each case, the use of cassette dosing is recommended in appropriate chemical series to enhance the efficiency of drug discovery and reduce animal usage. [Mol Cancer Ther 2007;6(2):428 -40]

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Section: Dmpk In Drug Discoverymentioning

confidence: 99%

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Smith

Raynaud

Workman

2007

Molecular Cancer Therapeutics

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“…18 Despite this, there are several short cyclic peptide based drugs on the market such as cilengitide 19 and eptifibatide. 20 For this study, we used a library of cyclic peptides against a large panel of proteinprotein and protein-peptide interactions represents a reverse of the standard virtual screening approach -using a tailored library of compounds to find protein targets amenable to modulation.…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening Using Combinatorial Cyclic Peptide Libraries Reveals Protein Interfaces Readily Targetable by Cyclic Peptides

Duffy

O'Donovan

Devocelle

et al. 2015

J. Chem. Inf. Model.

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Protein–protein and protein–peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein–protein and protein–peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein–protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical “hot spot” interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.

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“…The parallel LC/MS system is capable of analyzing up to 240 samples per hour and permits the complete profiling up to two microtiter plates of compounds per day (i.e., 176 test substrate compounds ϩ sixteen controls). (J Am Soc Mass Spectrom 2002, 13, 155-165) © 2002 American Society for Mass Spectrometry A dvances in directed parallel synthesis and high throughput screening (HTS) have enabled large numbers of biochemically potent (active) and selective compounds to be identified at early stages of drug discovery [1][2][3]. However, the fact that a compound is active and selective does not necessarily make it an attractive drug development candidate.…”

mentioning

confidence: 99%

“…To convert these lead candidates into druggable molecules has proved elusive. It has been reported that a disproportionately large number of compounds entering development fail because of poor pharmacokinetics (nearly 40%) [3][4][5]. Consequently, it has been recognized that pharmacokinetic studies that assess absorption, distribution, metabolism, and elimination (ADME) should be initiated as early as possible in the discovery process in order to maximize the likelihood of development success and minimize development costs.…”

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confidence: 99%

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Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries

Nemes

Jenkins

et al. 2002

J. Am. Soc. Mass Spectrom.

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Solution-phase and solid-phase parallel synthesis and high throughput screening have enabled biologically active and selective compounds to be identified at an unprecedented rate. The challenge has been to convert these hits into viable development candidates. To accelerate the conversion of these hits into lead development candidates, early assessment of the physicochemical and pharmacological properties of these compounds is being made. In particular, in vitro absorption, distribution, metabolism, and elimination (ADME) assays are being conducted at earlier and earlier stages of discovery with the goal of reducing the attrition rate of these potential drug candidates as they progress through development. In this report, we present an eight-channel parallel liquid chromatography/mass spectrometry (LC/MS) system in combination with custom Visual Basic and Applescript automated data processing applications for high throughput early ADME. The parallel LC/MS system was configured with one set of gradient LC pumps and an eight-channel multiple probe autosampler. The flow was split equivalently into eight streams before the multiple probe autosampler and recombined after the eight columns and just prior to the mass spectrometer ion source. The system was tested for column-to-column variation and for reproducibility over a 17 h period (approximately 500 injections per column). The variations in retention time and peak area were determined to be less than 2 and 10%, respectively, in both tests. The parallel LC/MS system described permits time-course microsomal incubations (t o , t 5 , t 15 , t 30 ) to be measured in triplicate and enables estimations of t 1/2 microsomal stability. The parallel LC/MS system is capable of analyzing up to 240 samples per hour and permits the complete profiling up to two microtiter plates of compounds per day (i.e., 176 test substrate compounds ϩ sixteen controls). (J Am Soc Mass Spectrom 2002, 13, 155-165) © 2002 American Society for Mass Spectrometry A dvances in directed parallel synthesis and high throughput screening (HTS) have enabled large numbers of biochemically potent (active) and selective compounds to be identified at early stages of drug discovery [1][2][3]. However, the fact that a compound is active and selective does not necessarily make it an attractive drug development candidate. To convert these lead candidates into druggable molecules has proved elusive. It has been reported that a disproportionately large number of compounds entering development fail because of poor pharmacokinetics (nearly 40%) [3][4][5]. Consequently, it has been recognized that pharmacokinetic studies that assess absorption, distribution, metabolism, and elimination (ADME) should be initiated as early as possible in the discovery process in order to maximize the likelihood of development success and minimize development costs. More and more, discovery programs are taking advantage of high throughput in vitro assays and property-based design tools to assist medicinal chemists in making not only poten...

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Managing the drug discovery/development interface

Cited by 483 publications

References 3 publications

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

Virtual Screening Using Combinatorial Cyclic Peptide Libraries Reveals Protein Interfaces Readily Targetable by Cyclic Peptides

Application of parallel liquid chromatography/mass spectrometry for high throughput microsomal stability screening of compound libraries

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