Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)

Ding, Yun; O’Keefe, Heather; DeLorey, Jennifer L.; Israel, David I.; Messer, Jeffrey A.; Chiu, Cynthia H.; Skinner, Steven R.; Matico, Rosalie; Murray-Thompson, Monique F.; Li, Fan; Clark, Matthew; Cuozzo, John W.; Arico-Muendel, Christopher C.; Morgan, Barry A.

doi:10.1021/acsmedchemlett.5b00138

Cited by 75 publications

(70 citation statements)

References 22 publications

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“…A handful of studies now exist describing the preparation and screening of solution-phase libraries that incorporate diverse reactions—including those rehearsed above—though only with conversion yield data. 20–23,32–34 We sought to determine whether our assay could be extensible to the investigation of solution-phase DNA-encoded reaction development, and whether and how those data could apply to solution-phase library planning and synthesis.…”

Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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DNA-encoded synthesis can generate vastly diverse screening libraries of arbitrarily complex molecules as long as chemical reaction conditions do not compromise DNA’s informational integrity, a fundamental constraint that “DNA-compatible” reaction development does not presently address. We devised DNA-encoded reaction rehearsal, an integrated analysis of reaction yield and impact on DNA, to acquire these key missing data. Magnetic DNA-functionalized sensor beads quantitatively report the % DNA template molecules remaining viable for PCR amplification after exposure to test reaction conditions. Analysis of solid-phase bond forming (e.g., Suzuki-Miyaura cross-coupling, reductive amination) and deprotection reactions (e.g., allyl esters, silyl ethers) guided the definition and optimization of DNA-compatible reaction conditions (> 90% yield, > 30% viable DNA molecules), most notably in cases that involved known (H+, Pd) and more obscure (Δ, DMF) hazards to DNA integrity. The data provide an empirical yet mechanistically consistent and predictive framework for designing successful DNA-encoded reaction sequences for combinatorial library synthesis.

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Section: Resultsmentioning

confidence: 99%

What is a “DNA-Compatible” Reaction?

2016

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“…The scope of Michael acceptors (Fig. 3A) was probed first; to this end, acrylates (12,16), acrylamides (17), vinyl ketones (13), acrylonitriles (14), and vinyl sulfones (15) were all found to be competent radical acceptors. Both α-substituted (18-24) and β-substituted (26,27) acceptors could be employed in this protocol, providing the Giese products in excellent yields.…”

Section: Significancementioning

confidence: 99%

“…In this way, libraries of incredible size (up to >10 9 members) could be procured and screened at once (rather than one by one in traditional combinatorial chemistry) with the ultimate vision of democratizing the practice of medicinal chemistry (10)(11)(12)(13)(14)(15). The vision and principles outlined therein are only recently being realized with advances in analysis and chemoselective synthesis, setting the stage for the widespread adoption of DEL-based discovery platforms in the pharmaceutical arena (16)(17)(18)(19)(20). DNA-compatible synthesis provides exciting challenges (21)(22)(23), particularly as most traditional techniques are not amenable to the idiosyncratic requirements of such systems (24,25).…”

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confidence: 99%

Kinetically guided radical-based synthesis of C(sp ³ )−C(sp ³ ) linkages on DNA

Wang

Lundberg

Asai

et al. 2018

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

134

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DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp)-C(sp) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.

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“…Nuevolution announced having created a 40 trillion member library of unique molecules, possibly the largest synthetic chemical library in the world at the time . Novel compounds exhibiting nanomolar potency have been selected through this strategy . Recently, several ligands for GPCRs were also selected from a DEL .…”

Section: Introductionmentioning

confidence: 99%

Functionality‐Independent DNA Encoding of Complex Natural Products

et al. 2019

Angewandte Chemie

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DNA encoded chemical libraries (DELs) link the powers of genetics and chemical synthesis via combinatorial optimization. Through combinatorial chemistry, DELs can grow to the unprecedented size of billions to trillions. To take full advantage of the DEL approach, linking the power of genetics directly to chemical structures would offer even greater diversity in a finite chemical world. Natural products have evolved an incredible structural diversity along with their biological evolution. Herein, we used traditional Chinese medicines (TCMs) as examples in a late‐stage modification toolbox approach to annotate these complex organic compounds with amplifiable DNA barcodes, which could be easily incorporated into a DEL. The method of end‐products labeling also generates a cluster of isomers with a single DNA tag at different sites. These isomers provide an additional spatial diversity for multiple accessible pockets of targeted proteins. Notably, a novel PARP1 inhibitor from TCM has been identified from the natural products enriched DEL (nDEL).

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Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)

Cited by 75 publications

References 22 publications

What is a “DNA-Compatible” Reaction?

What is a “DNA-Compatible” Reaction?

Kinetically guided radical-based synthesis of C(sp ³ )−C(sp ³ ) linkages on DNA

Functionality‐Independent DNA Encoding of Complex Natural Products

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Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)

Cited by 75 publications

References 22 publications

What is a “DNA-Compatible” Reaction?

What is a “DNA-Compatible” Reaction?

Kinetically guided radical-based synthesis of C(sp 3 )−C(sp 3 ) linkages on DNA

Functionality‐Independent DNA Encoding of Complex Natural Products

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Kinetically guided radical-based synthesis of C(sp ³ )−C(sp ³ ) linkages on DNA