Discovery of Thieno[3,2‑<i>d</i>]pyrimidine-6-carboxamides as Potent Inhibitors of SIRT1, SIRT2, and SIRT3

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD⁺ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., <b>11c</b>: IC₅₀ = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues <b>28</b> and <b>31</b>. Crystallographic studies of <b>11c</b>, <b>28</b>, and <b>31</b> bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein

Discovery of Highly Potent and Selective Small Molecule ADAMTS‑5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT)

The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (<i>R</i>)-<i>N</i>-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)­thiazol-4-yl)­methyl)­amino)-1,3,5-triazin-2-yl)­pyrrolidin-2-yl)­methyl)-4-propylbenzenesulfonamide (<b>8)</b>, inhibited ADAMTS-5 with IC₅₀ = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds <b>8</b> and <b>15f</b> inhibited aggrecanase-mediated ³⁷⁴ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1β/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation