8 research outputs found
Novel Catalyst System for Suzuki-Miyaura Coupling of Challenging DNA-Linked Aryl Chlorides
A novel Pd catalyst
system, [(<i>t</i>-Bu)<sub>2</sub>P(OH)]<sub>2</sub>PdCl<sub>2</sub> (POPd) with the ligand sodium
2′-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1′-biphenyl]-3-sulfonate,
is reported. It effectively catalyzes the Suzuki-Miyaura coupling
of challenging phenyl chlorides and pyrimidinyl chlorides that are
covalently linked to a double-stranded DNA-template with various boronic
acids/esters
Development and Synthesis of DNA-Encoded Benzimidazole Library
Encoded library technology
(ELT) is an effective approach to the
discovery of novel small-molecule ligands for biological targets.
A key factor for the success of the technology is the chemical diversity
of the libraries. Here we report the development of DNA-conjugated
benzimidazoles. Using 4-fluoro-3-nitrobenzoic acid as a key synthon,
we synthesized a 320 million-member DNA-encoded benzimidazole library
using Fmoc-protected amino acids, amines and aldehydes as diversity
elements. Affinity selection of the library led to the discovery of
a novel, potent and specific antagonist of the NK3 receptor
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 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
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 μM and Bcl-xL at >99 μM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 μM and Bcl-xL at >99 μM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h
Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of <i>Mycobacterium tuberculosis</i> InhA
Tuberculosis
(TB) is one of the world’s oldest and deadliest
diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase
from <i>Mycobacterium tuberculosis</i>, is the target of
the frontline antitubercular drug isoniazid (INH). Compounds that
directly target InhA and do not require activation by mycobacterial
catalase peroxidase KatG are promising candidates for treating infections
caused by INH resistant strains. The application of the encoded library
technology (ELT) to the discovery of direct InhA inhibitors yielded
compound <b>7</b> endowed with good enzymatic potency but with
low antitubercular potency. This work reports the hit identification,
the selected strategy for potency optimization, the structure–activity
relationships of a hundred analogues synthesized, and the results
of the in vivo efficacy studies performed with the lead compound <b>65</b>
Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action
ATAD2
(ANCCA) is an epigenetic regulator and transcriptional cofactor,
whose overexpression has been linked to the progress of various cancer
types. Here, we report a DNA-encoded library screen leading to the
discovery of BAY-850, a potent and isoform selective inhibitor that
specifically induces ATAD2 bromodomain dimerization and prevents interactions
with acetylated histones <i>in vitro</i>, as well as with
chromatin in cells. These features qualify BAY-850 as a chemical probe
to explore ATAD2 biology