The Impact of Combinatorial Methodologies on Medicinal Chemistry

Sánchez‐Martín, Rosario M.; Mittoo, Stifun; Bradley, Mark

doi:10.2174/1568026043451113

Cited by 46 publications

(24 citation statements)

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“…In light of these studies (145)(146)(147)(148)(149)(150), β-asparaginyladenylate 5 ( Figure 6) was synthesized (153) The relatively lengthy synthetic route to obtain this compound and the presence of a charged phosphoamidate functional group argue against its likely clinical utility. In addition, the coupling reaction was insufficiently robust for use in constructing molecular libraries that could be assayed for ASNS inhibitory activity using modern highthroughput screening methods (154)(155)(156)(157).…”

Section: Sulfonamide Derivatives As Inhibitors Of Human Asparagine Symentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

204

221

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Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzymebased methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.

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Section: Sulfonamide Derivatives As Inhibitors Of Human Asparagine Symentioning

confidence: 99%

Asparagine Synthetase Chemotherapy

Richards

Kilberg

2006

Annu. Rev. Biochem.

204

221

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“…At Novartis, fractionated natural product extracts continue to play a key role in discovery efforts. Alternatively, combinatorial collections have been constructed where thousands of slight variations are made around a central scaffold in an attempt to densely cover structure-activity relationships (SAR) within a narrow region of chemical property space (Sanchez-Martin et al, 2004). Overtime, a significant amount of bioassay data has accumulated on compound libraries leading to both private and public databases that provide an archeological footprint of past discovery efforts.…”

Section: Introductionmentioning

confidence: 99%

Composition and applications of focus libraries to phenotypic assays

Wassermann¹,

Camargo²,

Auld³

2014

Front. Pharmacol.

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The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these.

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“…The traditional approach of organic synthesis to sequentially synthesise a logically designed set of analogues based on a lead compound has been surpassed by the ability to screen whole compound libraries accumulated over the years by large pharmaceutical companies. Therefore, with the combinatorial strategy the productivity has been amplified beyond the levels obtained as routine in the last century [29,30].…”

Section: Figurementioning

confidence: 99%

“…Dynamic combinatorial chemistry [29,73,74] is based on continuous interconversion between the library constituents, it uses reversible connections between the initial building blocks producing flexible and adaptive libraries. This approach is driven by the interactions of the library constituents with the target site.…”

Section: Solid-phase and Solution-phase Combinatorial Chemistrymentioning

confidence: 99%