Targeting non-alcoholic fatty liver disease: Design, X-ray co-crystal structure and synthesis of ‘first-in-kind’ inhibitors of serine/threonine kinase25

Kiyeleko, Scarlett; Hocine, Sofiane; Mautino, Giséle; Kuenemann, Mélaine A.; Nawrotek, Agata; Miallau, L.; Vuillard, Laurent-Michel; Mirguet, Olivier; Kotschy, András; Hanessian, Stephen

doi:10.1016/j.bmcl.2022.128950

Cited by 3 publications

(4 citation statements)

References 44 publications

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“…While the chemical inhibition of IRF5 remains an efficacious therapeutic strategy, the modulation of IRF5 kinases represents an important avenue for disrupting IRF5 function. The recent development of small molecule inhibitors of STK25 provides an invaluable research tool and represents an important step toward the production of clinically relevant therapeutic agents (39). Even though STK25 has never been directly implicated in the pathogenesis of SLE, the ability of STK25 to regulate the TLR-induced activation of IRF5 indicates that STK25 may contribute to the hyperactivated IRF5 phenotype in this disease.…”

Section: Discussionmentioning

confidence: 99%

STK25 is an IRF5 kinase that promotes TLR7/8-mediated inflammation

Rice,

Matta,

Wang

et al. 2023

Preprint

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Toll-like receptors (TLRs) represent a subset of pattern-recognition receptors (PRRs) employed by the innate immune system to detect pathogen-associated molecular patterns (PAMPs) and initiate the response to invading microbes. The transcription factor interferon regulatory factor 5 (IRF5) functions as an important mediator of the inflammatory response downstream of MyD88-dependent TLR activation. While the dysregulation of IRF5 activity has been implicated in the development of several autoimmune diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis, the factors that modulate TLR-induced IRF5 post-translational modifications (PTMs) are poorly understood. Therefore, the focus of this study was to identify and characterize the role(s) of novel kinases in the regulation of TLR7/8 signaling. We performed a kinome-wide siRNA screen in human THP-1 monocytic cells to identify mediators of TLR7/8-induced TNF-α and IL-6 production. We identified serine/threonine protein kinase 25 (STK25) as a positive regulator of proinflammatory cytokine release in response to TLR7/8 activation in human primary myeloid cells. We determined that STK25 phosphorylates IRF5in vitrovia multiple biochemical assays. Phosphopeptide mapping by mass spectrometry revealed that STK25 phosphorylates IRF5 at a highly conserved residue, Thr265, that leads to the transcriptional activation of IRF5 in HEK293T cells. We determined that STK25 undergoes autophosphorylation in response to a variety of TLR triggers in multiple immune cell types. We demonstrated that R848-induced IRF5 nuclear translocation and proinflammatory cytokine production was significantly attenuated in immune cells fromStk25-deficient mice compared to wild-type. Finally, we determined that STK25 autophosphorylation is increased at steady-state in peripheral blood mononuclear cells (PBMCs) from SLE donors compared to healthy controls. Thus, our findings implicate STK25 as an important regulator of TLR7/8 signaling through the modulation of IRF5 activation.Significance StatementThe transcription factor IRF5 functions as a master regulator of innate and adaptive immunity. While the hyperactivation of IRF5 has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), the mechanisms leading to the modulation of IRF5 activity are incompletely understood. Here, we conducted a screen of the human kinome to identify IRF5 kinases that function as positive regulators of TLR-induced inflammation. We demonstrate that STK25 directly phosphorylates IRF5 to drive proinflammatory cytokine responses downstream of TLR activation in both human and murine primary immune cells. Altogether, our findings implicate STK25 as a potential therapeutic target for the management of IRF5-mediated immunological disorders.

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Section: Discussionmentioning

confidence: 99%

STK25 is an IRF5 kinase that promotes TLR7/8-mediated inflammation

Rice,

Matta,

Wang

et al. 2023

Preprint

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“…The protocol typically includes activation with oxalyl chloride, [232,233] followed by base-promoted reaction with N-or O-nucleophile (Scheme 36). In this way, SO 2 Clcontaining amides derived from anilines [234][235][236] (including oaminophenol [237] ), heteroaromatic [238,239] and aliphatic [234,[240][241][242][243] amines, hydrazides, [244] and hydroxamic acids [245] were obtained. Analogously, SO 2 Cl-substituted esters were synthesized from alcohols, [246][247][248] phenols, [249][250][251] or heterocyclic hydroxy derivatives.…”

Section: Reactions Tolerating the So 2 CL Moietymentioning

confidence: 99%

Chemoselective Reactions of Functionalized Sulfonyl Halides

Liashuk,

Andriashvili,

Tolmachev

et al. 2023

The Chemical Record

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Chemoselective transformations of functionalized sulfonyl fluorides and chlorides are surveyed comprehensively. It is shown that sulfonyl fluorides provide an excellent selectivity control in their reactions. Thus, numerous conditions are tolerated by the SO2F group – from amide and ester formation to directed ortho‐lithiation and transition‐metal‐catalyzed cross‐couplings. Meanwhile, sulfur (VI) fluoride exchange (SuFEx) is also compatible with numerous functional groups, thus confirming its title of “another click reaction”. On the contrary, with a few exceptions, most transformations of functionalized sulfonyl chlorides typically occur at the SO2Cl moiety.

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“…Staurosporine, a kinase inhibitor, has been used as a test standard in inhibiting STK25. Kiyeleko et al obtained a series of STK25 inhibitors by attaching a p-N-pyrrolidinosulphonamide group to the arylamine group [48]. Regrettably, STK25 is a relatively new target.…”

Section: Potential Drugs That May Target Stk25mentioning

confidence: 99%

“…Kiyeleko et al . obtained a series of STK25 inhibitors by attaching a p-N-pyrrolidinosulphonamide group to the arylamine group [48]. Regrettably, STK25 is a relatively new target.…”

Section: Potential Drugs That May Target Stk25mentioning

confidence: 99%

STK25: a viable therapeutic target for cancer treatments?

Chen

Lei

et al. 2022

Anti-Cancer Drugs

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Serine/threonine protein kinase 25 (STK25) is a critical regulator of ectopic lipid storage, glucose and insulin homeostasis, fibrosis, and meta-inflammation. More and more studies have revealed a strong correlation between STK25 and human diseases. On the one hand, STK25 can affect glucose and fatty acid metabolism in normal cells or tumors. On the other hand, STK25 participates in autophagy, cell polarity, cell apoptosis, and cell migration by activating various signaling pathways. This article reviews the composition and function of STK25, the energy metabolism and potential drugs that may target STK25, and the research progress of STK25 in the occurrence and development of tumors, to provide a reference for the clinical treatment of tumors.

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Targeting non-alcoholic fatty liver disease: Design, X-ray co-crystal structure and synthesis of ‘first-in-kind’ inhibitors of serine/threonine kinase25

Cited by 3 publications

References 44 publications

STK25 is an IRF5 kinase that promotes TLR7/8-mediated inflammation

STK25 is an IRF5 kinase that promotes TLR7/8-mediated inflammation

Chemoselective Reactions of Functionalized Sulfonyl Halides

STK25: a viable therapeutic target for cancer treatments?

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