DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules

Daguer, Jean‐Pierre; Zambaldo, Claudio; Ciobanu, Mihai; Morieux, Pierre; Barluenga, Sofía; Winssinger, Nicolas

doi:10.1039/c4sc01654h

Cited by 79 publications

(74 citation statements)

References 39 publications

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“…[7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay.…”

mentioning

confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

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confidence: 99%

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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“…In addition, peptide nucleic acid (PNA) encoding has been pursued on the basis that its encoding chemistry utilizes SPPS that it is compatible with co-synthesis of peptides and small molecule libraries. [33][34][35][36][37][38][39][40][41][42][43][44][45] Several studies have established that hybridization of PNAtagged molecules onto a DNA microarray can be used to rapidly identify the best binders within a library (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…1). 36,[44][45][46][47][48][49][50] We reasoned that this method could allow us to discriminate between covalent and non-covalent ligands using a denaturing wash that would denature proteins and compromise noncovalent ligand-protein interactions. However, aside from peptide-based libraries targeting proteases, 33,[37][38] no DNA or PNA-encoded library specifically designed to engage diverse protein targets in covalent interactions had been reported.…”

Section: Resultsmentioning

confidence: 99%

Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

et al. 2016

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DNA-encoded chemical libraries are increasingly used to identify leads for drug discovery or chemical biology. Despite the resurging interest in covalent inhibitors, libraries are typically designed with synthon filtered out for reactive functionalities that can engage a target through covalent interactions. Herein, we report the synthesis of two libraries containing Michael acceptors to identify cysteine reactive ligands. We developed a simple procedure to discriminate between covalent and high affinity non-covalent inhibitors using DNA display of the library in a microarray format. The methodology was validated with known covalent and high affinity non-covalent kinase inhibitors. Screening of the library revealed novel covalent inhibitors for MEK2 and ERBB2

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“…In a unique and powerful approach, the Winssinger group used DNA-immobilized, combinatorial fragment libraries to screen for novel inhibitors of Hsp70 [162]. By combining 125 biologically active fragments with 500 heterocycles on complementary DNA strands, they were able to assemble a microarray containing 62,500 combinations.…”

Section: Yk5mentioning

confidence: 99%

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Srinivasan

Shao

et al. 2015

Topics in Medicinal Chemistry

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Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein-protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

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DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules

Abstract: A focused library for Hsp70 was prepared from fragments identified from an array combinatorially pairing two libraries of small molecule fragments. Screening of the focus library yielded high affinity ligand to Hsp70.

Cited by 79 publications

References 39 publications

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Screening for covalent inhibitors using DNA-display of small molecule libraries functionalized with cysteine reactive moieties

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

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