Combinatorial synthesis — the design of compound libraries and their application to drug discovery

Terrett, N.K.; Gardner, Mark; Gordon, David W.; Kobylecki, Ryszard J.; Steele, John W.

doi:10.1016/0040-4020(95)00467-m

Cited by 647 publications

(217 citation statements)

References 67 publications

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“…peptide ligands can potentially lead to inactivation of kinase activity, CDKs represent particularly suitable targets for genetic [135] or chemical [136] peptide library approaches. One such approach, involving peptide aptamers, i.e.…”

Section: Peptide Library Approachesmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anticancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16 INK4 , p21 WAF1 , and p27 KIP1 , form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.

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Section: Peptide Library Approachesmentioning

confidence: 99%

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Fischer

Lane²

2000

CMC

141

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“…First, there have been major advances in areas like combinatorial synthesis (42,43). This has led to the development of highthroughput catalyst screens that may prove useful if the small-scale reactions can be generalized to preparative scale chemistry (44).…”

Section: Soluble Polymer-bound Catalysts and Substratesmentioning

confidence: 99%

Applications of polymeric smart materials to environmental problems.

Gray

Bergbreiter

1997

Environ Health Perspect

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“…Recently, combinatorial methods have been applied within several different areas of materials science, where increasing compositional or structural complexity often results in unique or otherwise improved properties (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Structural and compositional complexity may result in systems consisting of several components functioning cooperatively.…”

mentioning

confidence: 99%

Combinatorial discovery of oxidative dehydrogenation catalysts within the Mo-V-Nb-O system

Cong¹,

Dehestani²,

Doolen³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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Combinatorial methodologies were used for the synthesis and screening of mixed metal oxide heterogeneous catalysts. Primary screening at low reactant conversions at a throughput of greater than 10,000 catalyst compositions per month was performed by using simultaneous MS and photothermal def lection spectroscopy on spatially separated thick film catalysts with Ϸ200 g per catalyst prepared by using automated liquid dispensing. Secondary screening under realistic operating conditions was performed at a throughput of greater than 3,000 catalyst compositions per month on Ϸ50 mg of catalyst in an array of fixed bed microreactors with gas chromatograph detection. The approach was validated by the discovery of catalysts with superior performance to those previously described for the oxidative dehydrogenation of ethane to ethylene. We show the full implementation and integration of combinatorial methodologies for synthesis, screening, discovery, and optimization of multicomponent heterogeneous catalysts.Although combinatorial methodologies are practiced routinely for drug discovery (1, 2), this general approach is compelling in other fields where predictive abilities also are restricted. Recently, combinatorial methods have been applied within several different areas of materials science, where increasing compositional or structural complexity often results in unique or otherwise improved properties (1-12). Structural and compositional complexity may result in systems consisting of several components functioning cooperatively. In these combinations, the synergy of the multicomponent system results in performance characteristics that are particularly difficult to predict à priori. Presently, the vast majority of complex inorganic solids and multicomponent materials remain unexplored (13), in part because composition-structure-property relationships for such systems are limited. The utility of combinatorial chemistry, i.e., the ability both to prepare and to screen vast numbers of compounds in a rapid fashion, may be most productively realized within such systems. Here, we describe an integrated combinatorial program that has resulted in the discovery of improved multicomponent heterogeneous catalysts for the oxidative dehydrogenation of ethane to ethylene. Bringing combinatorial methodologies to bear on this application is particularly appealing because catalyst discovery has relied traditionally on an iterative trial-and-error synthesis and characterization strategy that is both tedious and time consuming.The parallel synthesis of catalytic materials by the use of automation and miniaturization techniques is most efficient when preparing very small quantities (Ͻ1 mg) of catalysts. The characterization of such small amounts of catalytic materials frequently is hindered by the lack of sensitive high throughput screening methodologies, particularly for reactions of low probability such as the partial oxidation of hydrocarbons. These obstacles have been overcome in our laboratories, and an integrated combinatorial d...

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Combinatorial synthesis — the design of compound libraries and their application to drug discovery

Cited by 647 publications

References 67 publications

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Inhibitors of Cyclin-Dependent Kinases as Anti-Cancer Therapeutics

Applications of polymeric smart materials to environmental problems.

Combinatorial discovery of oxidative dehydrogenation catalysts within the Mo-V-Nb-O system

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