Discovery of Sovleplenib, a Selective Inhibitor of Syk in Clinical Development for Autoimmune Diseases and Cancers
Spleen tyrosine kinase (Syk) is a cytosolic non-receptor protein tyrosine kinase and is mainly expressed in hematopoietic cells. Activation of Syk triggers multiple cellular responses and has been implicated in a variety of diseases. For this reason, Syk is considered a promising target for fighting autoimmune diseases, such as rheumatoid arthritis, immune thrombocytopenic purpura, and warm antibody hemolytic anemia, as well as hematological malignancies. The first Syk inhibitor approved by the Food and Drug Administration and European Medicines Agency was fostamatinib. However, considering the limitations of the currently available molecules, there is a need for novel Syk inhibitors with an improved profile.
In this issue, Jia et al. (DOI: 10.1021/acsmedchemlett.3c00553) describe an elegant
medicinal chemistry strategy that led to the
identification of the clinical candidate Syk inhibitor, sovleplenib.
An extensive structure–activity relationship study around the
pyrido[3,4-b]pyrazine scaffold allowed the authors
to pinpoint sovleplenib, which showed high potency, kinome selectivity,
desirable drug-like properties, and optimized pharmacokinetic properties.
In addition, sovleplenib reversed the disease progress in a mouse
model of arthritis. Altogether, these results supported the investigation
of the molecule in three different clinical trials for the treatment
of immune-mediated diseases and hematological tumors.
Discovery of Novel Binders to Sterol Regulatory Element-Binding Protein-1 by High-Throughput Screening
Sterol regulatory element binding protein (SREBP-1) is a membrane-bound transcription factor that controls the expression of several genes involved in cellular fatty acid synthesis. SREBP-1 levels are elevated in obese patients and in animal models of obesity and type 2 diabetes. Thus, SREBP-1 is an interesting therapeutic target for the treatment of obesity and associated metabolic diseases. Unfortunately, little is known on the function of SREBP-1 in the pathogenesis of these disorders, and this is connected to the lack of selective inhibitors.
In
this issue, Maruyama et al. (DOI: 10.1021/acsmedchemlett.4c00067) exploit the N-terminal region of human SREBP-1a
to identify small molecules that directly bind to SREBP-1. A high-throughput
screening using a thermal shift assay was used to assess the compounds’
effect on protein thermal stability. Afterward, surface plasmon resonance
led to the identification of two hit compounds based on affinity and
specificity. The novel human SREBP-1 binders could be further optimized
to develop specific SREBP-1 inhibitors for potential application in
the treatment of obesity and atherosclerotic diseases. In addition,
purified SREBP-1 might shed light on its architectural organization
and guide structure-based drug design.
Synthesis of Monofluorinated 7-Hydroxycoumarin-3-Carboxamides as Cell-Permeable Fluorescent Molecular Probes
The measurement and quantification of target engagement in living cells is currently a pivotal component of drug discovery programs. In parallel to NanoBRET, which has been extensively applied to study small molecule-protein interactions in physiologically relevant environments, the fluorescent probe cellular binding assay (FPCBA) has been exploited for target engagement investigations. FPCBA requires a cell-permeable fluorophore that can be successfully detected by flow cytometry.
In this issue, Rane et al. (DOI: 10.1021/acsmedchemlett.4c00085) develop fluorinated derivatives of the fluorophore 7-hydroxycoumarin-3-carboxylic
acid (7OHCCA) exploiting the ability of fluorine to modulate acidity
and brightness of 7OHCCA. The innovative fluorophores showed significantly
brighter fluorescence compared to one of the brightest commercially
available coumarins. Aiming to assess the effects on biological activity,
the authors synthesized new fluorescent analogues of the anticancer
drug paclitaxel. Interestingly, the acidity of the coumarin phenol
significantly affected cellular efflux and binding to microtubules
in living cells. The less acidic 6FC-GABA-Taxol turned out to be more
cell-permeable than the PB-GABA-Taxol due to a lower susceptibility
to active efflux. Overall, the excellent fluorescence brightness of
6FC derivatives together with their biological properties make this
monofluorinated fluorophore an excellent building block for the preparation
of cell-permeable chemical probes suitable for target engagement studies.