12 research outputs found
Small molecule SARM1 inhibitors recapitulate the SARM1 -/- phenotype and allow recovery of a metastable pool of axons fated to degenerate
Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM
Kinase Crystal Miner: A Powerful Approach to Repurposing 3D Hinge Binding Fragments and Its Application to Finding Novel Bruton Tyrosine Kinase Inhibitors
Protein kinases represent an important
target class for drug discovery
because of their role in signaling pathways involved in disease areas
such as oncology and immunology. A key element of many ATP-competitive
kinase inhibitors is their hinge-binding motif. Here, we describe
Kinase Crystal Miner (KCM)î¸a new approach developed at Boehringer
Ingelheim (BI) that harvests the existing crystallographic information
on kinase-inhibitor co-crystal structures from internal and external
databases. About 1000 unique three-dimensional kinase inhibitor hinge
binding motifs have been extracted from structures covering more than
180 different protein kinases. These hinge binding motifs along with
their attachment vectors have been combined in the KCM for the purpose
of scaffold hopping, kinase screening deck design, and interactive
structure-based design. Prospective scaffold hopping using the KCM
identified two potent and selective Bruton tyrosine kinase (BTK) inhibitors
with hinge binding fragments novel to BTK
Highly selective inhibition of Brutonâs tyrosine kinase attenuates skin and brain disease in murine lupus
Abstract Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects different end organs, including skin and brain. We and others have previously shown the importance of macrophages in the pathogenesis of cutaneous and neuropsychiatric lupus. Additionally, autoantibodies produced by autoreactive B cells are thought to play a role in both the skin and central nervous system pathologies associated with SLE. Methods We used a novel inhibitor of Brutonâs tyrosine kinase (BTK), BI-BTK-1, to target both macrophage and B cell function in the MRL-lpr/lpr murine model of SLE, and examined the effect of treatment on skin and brain disease. Results We found that treatment with BI-BTK-1 significantly attenuated the lupus associated cutaneous and neuropsychiatric disease phenotypes in MRL/lpr mice. Specifically, BI-BTK-1 treated mice had fewer macroscopic and microscopic skin lesions, reduced cutaneous cellular infiltration, and diminished inflammatory cytokine expression compared to control mice. BTK inhibition also significantly improved cognitive function, and decreased accumulation of T cells, B cells, and macrophages within the central nervous system, specifically the choroid plexus. Conclusions Directed therapies may improve the response rate in lupus-driven target organ involvement, and decrease the dangerous side effects associated with global immunosuppression. Overall, our results suggest that inhibition of BTK may be a promising therapeutic option for cutaneous and neuropsychiatric disease associated with SLE
Additional file 2: Figure S1. of Highly selective inhibition of BrutonâÂÂs tyrosine kinase attenuates skin and brain disease in murine lupus
Flow cytometry gating strategy. Cortical and choroid plexus tissue from MRL/lpr mice treated or not with BI-BTK-1 were analyzed by flow cytometric analysis. Red arrows denote sequential gated population (red boxes). Black arrows denote sequential non-gated population. (DOCX 358ĂÂ kb
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NAD+ cleavage activity by animal and plant TIR domains in cell death pathways.
SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways
Optimization of Drug-Like Properties of Nonsteroidal Glucocorticoid Mimetics and Identification of a Clinical Candidate
A series of nonsteroidal âdissociatedâ
glucocorticoid
receptor agonists was optimized for drug-like properties such as cytochrome
P450 inhibition, metabolic stability, aqueous solubility, and hERG
ion channel inhibition. This effort culminated in the identification
of the clinical candidate compound <b>(</b><i><b>R</b></i><b>)-39</b>
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NAD+ cleavage activity by animal and plant TIR domains in cell death pathways.
SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways
Early Development Scale-Up of a Structurally-Challenging 5âLipoxygenase Activating Protein (FLAP) Inhibitor
A practical
and efficient synthesis of the FLAP inhibitor <b>1</b> was developed
addressing multiple scale-up and safety concerns
posed by the established synthesis and utilized a resolution strategy
(replacing supercritical fluid chromatography (SFC) separation) for
expedient access to the key structural component of <b>1</b>: the challenging chiral quaternary center. Also highlighted are
in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring,
and an efficient Suzuki-Miyaura coupling