MAY 2024 – Identification of potent pan-ephrin receptor kinase inhibitors using DECL technology

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In this report, DNA-encoded chemical library screenings were used to develop potent, selective and nonhormonal inhibitors of the EPH receptor kinase family.  EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface–associated ligands. EPHA2 and EPHA4 expressions are increased in endometriotic lesions. Therefore, chemical inhibition of EPHA2/4 receptors could have … Read more

Highly Selective Novel Heme Oxygenase-1-Targeting Molecules Discovered by DECL-Machine Learning (ML) Model beyond the DECL Chemical Space

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A Machine Learning (ML) approach was integrated with DNA-encoded chemical library (DECL) screening to facilitate the identification of highly selective compounds targeting Heme oxygenase-1 (HO-1) compared to its counterpart, HO-2 (the ferric-heme bound form, Holo HO-2). HO-1 and HO-2 are principal enzymes within the HO family, known for their roles in inflammation and oxidative stress … Read more

2024 – Discovery of novel and potent indazole NLRP3 inhibitors enabled by DNA-encoded library screening

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In this report, multiple DNA-conjugate libraries, comprising a total of over 500 billion small molecular ligand candidates, have been selected to identify novel NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3) nanomolar inhibitors. NLRP3 activation results in a protective pro-inflammatory response by the release of the pro-inflammatory cytokines IL-1β and IL-18, subsequently … Read more

2023 – DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors

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In this communication, a 4-billion-membered DNA-conjugate library was used to identify non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Mpro is the SARS-CoV-2 main protease responsible for the liberation and maturation of proteins required for viral propagation. Furthermore, the newly discovered inhibitors demonstrate efficacy against mutant forms of Mpro that have … Read more

2023 – DECLs enable the development of BRET probes for target engagement studies in cells

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This work explores the applicability of a DNA-conjugate library for rapidly identifying and converting hits/ligands into corresponding bioluminescence resonance energy transfer (BRET) probes. Subsequently, a complementary workflow has been developed to validate and prioritize DECL hits using bioluminescence resonance energy transfer (BRET) in a living cellular context. The combination of DECL screening for generation of … Read more

2023 – A DECL based on 4-amino-proline enables stereospecific isozyme-selective protein recognition

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This article presents the design, synthesis, and characterization of a large DNA-conjugate library consisting of 3,735,936 members. The library features a stereo-defined 4-amino-proline central scaffold with two sets of carboxylic acid building blocks. Parallel screening methods, focusing on closely related proteins or isoforms of pharmaceutically relevant protein targets (such as CAIX, PSMA, and Nsp14) enabled … Read more

2023 – Trio-pharmacophore DNA-encoded chemical library for simultaneous selection of fragments and linkers

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A new trio-pharmacophore self-assembly DNA-encoded chemical library (T-DEL) comprising 883 x 30 x 890 members was assembled, validated and used for  the y de novo identifications of µM inhibitors of matrix metalloprotease-2 and −9. In this report a trio-pharmacophore DNA-encoded self-assembling chemical library (T-DEL) is generated by the DNA-hybridization of two single-strand DNA-encoded sub-libraries (SL) A and C on a third … Read more

2023 – Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DECL Screening

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In this publication, screening a 4.17 billion member DNA-conjugate library enabled the isolation of low-nanomolar selective inhibitors of kinase BMPR2. Bone morphogenetic proteins (BMPs) are highly conserved secreted ligands of the TGFβ family, playing critical roles in development, cell proliferation, differentiation, and apoptosis. Therefore, BMPs and their cognate receptors (BMPR1 and BMPR2) also play key … Read more

2022 – Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections

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A DNA-encoded chemical libraries (DECLs) containing billion of members was used to identify chiral BET BD1-selective inhibitors with high potency and cellular activity. Inhibition of two tandem bromodomains (BD1 and BD2) contained in bromodomain and extraterminal (BET) proteinslike BRDT, BRD2, BRD3, or BRD4, is a therapeutic avenue for the treatment of multiple diseases, like cancer, inflammation, infectious diseases … Read more

2022 – DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor

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One-Bead-One-Compound (OBOC) DNA-encoded library comprising 73,728 ligands was screened against a library of RNA structures (4,096 targets) to identify three-dimensional RNA hairpins target pairs.  One of the discovered ligands bound a 5’GAG/3’CCC RNA-loop that is present in primary microRNA-27a (pri-miR-27a), the oncogenic precursor of microRNA-27a. In this report from The Scripps Research Institute, DNA-tag encoding and Two-Dimensional Combinatorial Screening (2DCS) has … Read more