Novel encoding methods for DNA-templated chemical libraries

Li, Gang; Zheng, Wenlu; Liu, Ying; Li, Xiaoyü

doi:10.1016/j.cbpa.2015.01.004

Cited by 27 publications

(18 citation statements)

References 98 publications

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“…DNA encoded library (DEL) technology allows for facile generation and screening of extremely large numbers of drug-like molecules. − Numerous literature reports illustrate the value of the technology including the discovery of LFA-1, ADAMTS-5, RIP3 kinase, BCATm, InhA, SIRT1–3, Wip1 phosphatase, and sEH inhibitors. DNA encoded libraries (DELs) are commonly synthesized via split-and-pool chemistry, − although a variety of alternative methodologies have been reported. − Regardless of the method of synthesis, the technology results in the generation of complex mixtures of DNA conjugates. Each library member consists of a small-molecule moiety covalently tethered to a DNA sequence.…”

Section: Introductionmentioning

confidence: 99%

“…The DNA sequence, or barcode, encodes the protocol for the multistep chemical synthesis of the attached small molecule. Generally, the multistep synthesis consists of aqueous and DNA-compatible reactions, which allow access to drug-like small molecules. − It is generally not possible to remove unreacted starting materials or byproducts during library synthesis or to quantify the yields of the products and byproducts. − Thus, the final population of library members with a particular barcode will include many related but different small molecules . The ratios of the different products is dictated by the synthetic yields at each step of the multistep synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Satz

2016

ACS Comb. Sci.

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Simulated screening of DNA encoded libraries indicates that the presence of truncated byproducts complicates the relationship between library member enrichment and equilibrium association constant (these truncates result from incomplete chemical reactions during library synthesis). Further, simulations indicate that some patterns observed in reported experimental data may result from the presence of truncated byproducts in the library mixture and not structure-activity relationships. Potential experimental methods of minimizing the presence of truncates are assessed via simulation; the relationship between enrichment and equilibrium association constant for libraries of differing purities is investigated. Data aggregation techniques are demonstrated that allow for more accurate analysis of screening results, in particular when the screened library contains significant quantities of truncates.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simulated Screens of DNA Encoded Libraries: The Potential Influence of Chemical Synthesis Fidelity on Interpretation of Structure–Activity Relationships

Satz

2016

ACS Comb. Sci.

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“…As such, the generation and downstream purification of these libraries prior to use in HTS is of utmost importance. The chemistries applied in these processes are beyond the scope of this review, but they have been reviewed elsewhere (Favalli, Bassi, Scheuermann, & Neri, 2018;Franzini et al, 2015;Goodnow Jr. et al, 2017;Li, Zheng, Liu, & Li, 2015).…”

Section: Dna-encoded Compound Libraries (Decls)mentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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“…33–42 In contrast to DCLs, due to DNA's high encoding capacity, DELs can contain millions of different compounds; 43–46 library selection can be feasibly decoded using PCR amplification and DNA sequencing. 47,48 Therefore, introducing DNA-encoding to DCLs could be an effective strategy to address the limitation of their library size.…”

Section: Introductionmentioning

confidence: 99%