Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library

Dawadi, Surendra; Simmons, Nicholas; Miklóssy, Gabriella; Bohren, Kurt M.; Faver, John C.; Ucisik, Melek N.; Nyshadham, Pranavanand; Yu, Zhifeng; Matzuk, Martin M.

doi:10.1073/pnas.2005447117

Cited by 49 publications

(35 citation statements)

References 39 publications

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“…Using a split-and-pool strategy, each individual library of ∼100 million compounds was synthesized with a unique core scaffold. Quality assurance of libraries for selections was ensured through optimization and validation of on-DNA chemistry reactions prior to library synthesis and the precision of our DNA barcode reads using Illumina sequencing after library synthesis ( 13 , 20 – 22 ). These individual DEC-Tec libraries were subsequently pooled and screened as multibillion compound mixtures against His-tagged recombinant bromodomain proteins.…”

Section: Resultsmentioning

confidence: 99%

“…DEC-Tec has been utilized by several pharmaceutical companies and academic institutions to develop potent and specific small-molecule inhibitors to various target proteins, including EPHX2 ( 7 ), RIP1 kinase ( 8 ), Mycobacterium tuberculosis InhA ( 9 ), autotaxin ( 10 ), BTK ( 11 ), the β 2 -adrenergic receptor ( 12 ), etc. Using the libraries that we created, our DEC-Tec screening against thrombin ( 13 ) and OXA-48 carbapenemase ( 14 ) also resulted in nanomolar small-molecule inhibitors for further development.…”

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confidence: 99%

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Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

Anglin

et al. 2021

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

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Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined for their ability to compete with JQ1 in BRDT and BRD4 bromodomain AlphaScreen assays. These studies identified CDD-1102 as a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Structure–activity relationship studies of CDD-1102 produced a series of additional BRDT-BD2/BRD4-BD2 selective inhibitors, including CDD-1302, a truncated analog of CDD-1102 with similar activity, and CDD-1349, an analog with sixfold selectivity for BRDT-BD2 versus BRD4-BD2. BROMOscan bromodomain profiling confirmed the great affinity and selectivity of CDD-1102 and CDD-1302 on all BET BD2 versus BD1 with the highest affinity for BRDT-BD2. Cocrystals of BRDT-BD2 with CDD-1102 and CDD-1302 were determined at 2.27 and 1.90 Å resolution, respectively, and revealed BRDT-BD2 specific contacts that explain the high affinity and selectivity of these compounds. These BD2-specific compounds and their binding to BRDT-BD2 are unique compared with recent reports and enable further evaluation of their nonhormonal contraceptive potential in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

Anglin

et al. 2021

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

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“…Whereas, Cuozzo et al screened a DECL library of 225 million compounds, and identified a single compound (X-165) with a high activity against the production of lysophosphatidic acid, and this compound has been approved by the FDA for Phase I Clinical trials [197]. In other examples of using this strategy, Dawadi et al discovered a thrombin inhibitor using DECL [198], while, Kung et al identified two compounds that presented inhibition/binders to e Nα-terminal acetyltransferase (Naa50) using ECL library screening [199].…”

Section: Compound Screeningmentioning

confidence: 99%

Microarrays and NGS for Drug Discovery

Pop¹,

Zănoagă²,

Chiroi³

et al. 2021

Drug Design - Novel Advances in the Omics Field and Applications

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Novel technologies and state of the art platforms developed and launched over the last two decades such as microarrays, next-generation sequencing, and droplet PCR have provided the medical field many opportunities to generate and analyze big data from the human genome, particularly of genomes altered by different diseases like cancer, cardiovascular, diabetes and obesity. This knowledge further serves for either new drug discovery or drug repositioning. Designing drugs for specific mutations and genotypes will dramatically modify a patient’s response to treatment. Among other altered mechanisms, drug resistance is of concern, particularly when there is no response to cancer therapy. Once these new platforms for omics data are in place, available information will be used to pursue precision medicine and to establish new therapeutic guidelines. Target identification for new drugs is necessary, and it is of great benefit for critical cases where no alternatives are available. While mutational status is of highest importance as some mutations can be pathogenic, screening of known compounds in different preclinical models offer new and quick strategies to find alternative frameworks for treating more diseases with limited therapeutic options.

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“…Trypsin and thrombin : Focused split‐and‐pool DNA‐encoded libraries were designed by the groups of Neri and Matzuk, respectively, around the oxyanion hole‐binders benzamidine and guanidine to probe the surface around the active site of the serine proteases trypsin and thrombin, respectively. Successful identification of nanomolar inhibitors of trypsin 27 (Figure 7), and thrombin 28 (Figure 7), showed the potential of combinatorial libraries to identify highly potent protease inhibitors by densely covering chemical space around weakly active starting points [131,132] …”

Section: Proteasesmentioning

confidence: 99%

Scanning Protein Surfaces with DNA‐Encoded Libraries

et al. 2020

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Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug‐like compounds on any site, can give important stimuli to drug‐development projects. For instance, inhibition of protein–protein interactions usually depends on the identification of protein surface binders. DNA‐encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein–protein interaction inhibitors and compounds binding to the surface of G protein‐coupled receptors (GPCRs) and kinases. The protein surface‐binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small‐molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target‐focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment‐like, starting points.

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Discovery of potent thrombin inhibitors from a protease-focused DNA-encoded chemical library

Cited by 49 publications

References 39 publications

Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

Discovery and characterization of bromodomain 2–specific inhibitors of BRDT

Microarrays and NGS for Drug Discovery

Scanning Protein Surfaces with DNA‐Encoded Libraries

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