17 research outputs found
MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition
The nucleotide-binding-domain (NBD)-and leucine-rich repeat (LRR)-containing (NLR) family, pyrin-domain-containing 3 (NLRP3) inflammasome drives pathological inflammation in a suite of autoimmune, metabolic, malignant, and neurodegenerative diseases. Additionally, NLRP3 gain-of-function point mutations cause systemic periodic fever syndromes that are collectively known as cryopyrin-associated periodic syndrome (CAPS). There is significant interest in the discovery and development of diarylsulfonylurea Cytokine Release Inhibitory Drugs (CRIDs) such as MCC950/CRID3, a potent and selective inhibitor of the NLRP3 inflammasome pathway, for the treatment of CAPS and other diseases. However, drug discovery efforts have been constrained by the lack of insight into the molecular target and mechanism by which these CRIDs inhibit the NLRP3 inflammasome pathway. Here, we show that the NAIP, CIITA, HET-E, and TP1 (NACHT) domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors. Interestingly, we find photoaffinity labeling (PAL) of the NACHT domain requires an intact (d)ATP-binding pocket and is substantially reduced for most CAPS-associated NLRP3 mutants. In concordance with this finding, MCC950/CRID3 failed to inhibit NLRP3-driven inflammatory pathology in two mouse models of CAPS. Moreover, it abolished circulating levels of interleukin (IL)-1 beta and IL-18 in lipopolysaccharide (LPS)-challenged wild-type mice but not in Nlrp3(L351P) knock-in mice and ex vivo-stimulated mutant macrophages. These results identify wild-type NLRP3 as the molecular target of MCC950/CRID3 and show that CAPS-related NLRP3 mutants escape efficient MCC950/CRID3 inhibition. Collectively, this work suggests that MCC950/CRID3-based therapies may effectively treat inflammation driven by wild-type NLRP3 but not CAPS-associated mutants
A General Strategy for the Construction of Functionalized Azaindolines via Domino Palladium-Catalyzed Heck Cyclization/Suzuki Coupling
The preparation of substituted azaindolines
utilizing a domino
palladium-catalyzed Heck cyclization/Suzuki coupling is described.
The approach is amenable for the construction of all four azaindoline
isomers. A range of functional groups such as esters, amides, ketones,
sulfones, amines, and nitriles are all tolerated under the reaction
conditions
Heteroarylation of Azine <i>N</i>-Oxides
Azine <i>N</i>-oxides undergo highly regioselective metalation with TMPZnCl·LiCl under mild conditions. A palladium-catalyzed Negishi cross-coupling reaction of the resulting organozinc species with heteroaromatic bromides provides heterobiaryls specifically oxidized at one nitrogen position in up to 95% yield
Correction: MCC950/CRID3 potently targets the NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome inhibition.
[This corrects the article DOI: 10.1371/journal.pbio.3000354.]
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
A novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ
The Rational Design of Selective Benzoxazepin Inhibitors of the α‑Isoform of Phosphoinositide 3‑Kinase Culminating in the Identification of (<i>S</i>)‑2-((2-(1-Isopropyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2‑<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)
Inhibitors of the class I phosphoinositide
3-kinase (PI3K) isoform
PI3Kα have received substantial attention for their potential
use in cancer therapy. Despite the particular attraction of targeting
PI3Kα, achieving selectivity for the inhibition of this isoform
has proved challenging. Herein we report the discovery of inhibitors
of PI3Kα that have selectivity over the other class I isoforms
and all other kinases tested. In GDC-0032 (<b>3</b>, taselisib),
we previously minimized inhibition of PI3Kβ relative to the
other class I insoforms. Subsequently, we extended our efforts to
identify PI3Kα-specific inhibitors using PI3Kα crystal
structures to inform the design of benzoxazepin inhibitors with selectivity
for PI3Kα through interactions with a nonconserved residue.
Several molecules selective for PI3Kα relative to the other
class I isoforms, as well as other kinases, were identified. Optimization
of properties related to drug metabolism then culminated in the identification
of the clinical candidate GDC-0326 (<b>4</b>)
Back Pocket Flexibility Provides Group II p21-Activated Kinase (PAK) Selectivity for Type I 1/2 Kinase Inhibitors
Structure-based
methods were used to design a potent and highly
selective group II p21-activated kinase (PAK) inhibitor with a novel
binding mode, compound <b>17</b>. Hydrophobic interactions within
a lipophilic pocket past the methionine gatekeeper of group II PAKs
approached by these type I 1/2 binders were found to be important
for improving potency. A structure-based hypothesis and strategy for
achieving selectivity over group I PAKs, and the broad kinome, based
on unique flexibility of this lipophilic pocket, is presented. A concentration-dependent
decrease in tumor cell migration and invasion in two triple-negative
breast cancer cell lines was observed with compound <b>17</b>