5 research outputs found
Design and Synthesis of Biaryl DNA-Encoded Libraries
DNA-encoded
library technology (ELT) is a powerful tool for the
discovery of new small-molecule ligands to various protein targets.
Here we report the design and synthesis of biaryl DNA-encoded libraries
based on the scaffold of 5-formyl 3-iodobenzoic acid. Three reactions
on DNA template, acylation, Suzuki–Miyaura coupling and reductive
amination, were applied in the library synthesis. The three cycle
library of 3.5 million diversity has delivered potent hits for phosphoinositide
3-kinase α (PI3Kα)
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
Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor
DNA-encoded small-molecule library
technology has recently emerged
as a new paradigm for identifying ligands against drug targets. To
date, this technology has been used with soluble protein targets that
are produced and used in a purified state. Here, we describe a cell-based
method for identifying small-molecule ligands from DNA-encoded libraries
against integral membrane protein targets. We use this method to identify
novel, potent, and specific inhibitors of NK3, a member of the tachykinin
family of G-protein coupled receptors (GPCRs). The method is simple
and broadly applicable to other GPCRs and integral membrane proteins.
We have extended the application of DNA-encoded library technology
to membrane-associated targets and demonstrate the feasibility of
selecting DNA-tagged, small-molecule ligands from complex combinatorial
libraries against targets in a heterogeneous milieu, such as the surface
of a cell
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)Âthiazol-4-yl)Âmethyl)Âamino)-1,3,5-triazin-2-yl)Âpyrrolidin-2-yl)Âmethyl)-4-propylbenzenesulfonamide
(<b>8)</b>, inhibited ADAMTS-5 with IC<sub>50</sub> = 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 <sup>374</sup>ARGS 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
Discovery, SAR, and X‑ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library
As a potential target for obesity,
human BCATm was screened against
more than 14 billion DNA encoded compounds of distinct scaffolds followed
by off-DNA synthesis and activity confirmation. As a consequence,
several series of BCATm inhibitors were discovered. One representative
compound (<i>R</i>)-3-((1-(5-bromothiophene-2-carbonyl)Âpyrrolidin-3-yl)Âoxy)-<i>N</i>-methyl-2′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxamide
(<b>15e</b>) from a novel compound library synthesized via on-DNA
Suzuki–Miyaura cross-coupling showed BCATm inhibitory activity
with IC<sub>50</sub> = 2.0 ÎĽM. A protein crystal structure of <b>15e</b> revealed that it binds to BCATm within the catalytic site
adjacent to the PLP cofactor. The identification of this novel inhibitor
series plus the establishment of a BCATm protein structure provided
a good starting point for future structure-based discovery of BCATm
inhibitors