Treatment with YKL-05-099, a salt inducible kinase (SIK) inhibitor, attenuates salt-sensitive hypertension: The molecular outcomes of SIK in the kidney.

Article

作者: Vallotton, Zoe ; Visniauskas, Bruna ; Lara, Lucienne S ; Katakam, Prasad V G ; Prieto, Minolfa C ; Lowe, Jennifer ; Taveira-da-Silva, Rosilane ; Gomes, Dayene S

Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na⁺ sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups - receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na⁺ balance was positive due, partly, to a higher (Na⁺+K⁺)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress. SIGNIFICANCE: Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.

2024-05-01·The Journal of biological chemistry

The structures of salt-inducible kinase 3 in complex with inhibitors reveal determinants for binding and selectivity

Article

作者: Öster, Linda ; Castaldo, Marie ; de Vries, Emma ; Cederblad, Linda ; Pemberton, Nils ; Käck, Helena ; Gordon, Euan ; Edfeldt, Fredrik

The salt-inducible kinases (SIKs) 1 to 3, belonging to the AMPK-related kinase family, serve as master regulators orchestrating a diverse set of physiological processes such as metabolism, bone formation, immune response, oncogenesis, and cardiac rhythm. Owing to its key regulatory role, the SIK kinases have emerged as compelling targets for pharmacological intervention across a diverse set of indications. Therefore, there is interest in developing SIK inhibitors with defined selectivity profiles both to further dissect the downstream biology and for treating disease. However, despite a large pharmaceutical interest in the SIKs, experimental structures of SIK kinases are scarce. This is likely due to the challenges associated with the generation of proteins suitable for structural studies. By adopting a rational approach to construct design and protein purification, we successfully crystallized and subsequently solved the structure of SIK3 in complex with HG-9-91-01, a potent SIK inhibitor. To enable further SIK3-inhibitor complex structures we identified an antibody fragment that facilitated crystallization and enabled a robust protocol suitable for structure-based drug design. The structures reveal SIK3 in an active conformation, where the ubiquitin-associated domain is shown to provide further stabilization to this active conformation. We present four pharmacologically relevant and distinct SIK3-inhibitor complexes. These detail the key interaction for each ligand and reveal how different regions of the ATP site are engaged by the different inhibitors to achieve high affinity. Notably, the structure of SIK3 in complex with a SIK3 specific inhibitor offers insights into isoform selectivity.

2024-01-01·International journal of biological sciences

Targeting phosphorylation circuits on CREB and CRTCs as the strategy to prevent acquired skin hyperpigmentation

Article

作者: An, Hyun Jin ; Kim, Youngoo ; Lee, Seung Wha ; Hwang, Bang Yeon ; Yun, Cheng-Yong ; Na, Changseon ; Jung, Jae-Kyung ; Kim, Song-Hee ; Lee, Jae Duk ; Han, Sang-Bae ; Kim, Jun Gu ; Baek, Seung Tae

Background: The cAMP response element-binding protein (CREB) and CREB-regulated transcription coactivators (CRTCs) cooperate in the transcriptional activation of microphthalmia-associated transcription factor subtype M (MITF-M) that is a master regulator in the biogenesis, pigmentation and transfer of melanosomes at epidermal melanocytes. Here, we propose the targeting of phosphorylation circuits on CREB and CRTCs in the expression of MITF-M as the rationale to prevent skin hyperpigmentation by elucidating the inhibitory activity and mechanism of yakuchinone A (Yaku A) on facultative melanogenesis. Methods: We employed human epidermal melanocyte cell, mouse skin, and mouse melanoma cell, and applied Western blotting, reverse transcription-polymerase chain reaction, immunoprecipitation and confocal microscopy to conduct this study. Results: This study suggested that α-melanocyte stimulating hormone (α-MSH)-induced melanogenic programs could switch on the axis of protein kinase A-salt inducible kinases (PKA-SIKs) rather than that of PKA-AMP activated protein kinase (PKA-AMPK) during the dephosphorylation of CRTCs in the expression of MITF-M. SIK inhibitors rather than AMPK inhibitors stimulated melanin production in melanocyte cultures in the absence of extracellular melanogenic stimuli, wherein SIK inhibitors increased the dephosphorylation of CRTCs but bypassed the phosphorylation of CREB for the expression of MITF-M. Treatment with Yaku A prevented ultraviolet B (UV-B)-irradiated skin hyperpigmentation in mice and inhibited melanin production in α-MSH- or SIK inhibitor-activated melanocyte cultures. Mechanistically, Yaku A suppressed the expression of MITF-M via dually targeting the i) cAMP-dependent dissociation of PKA holoenzyme at the upstream from PKA-catalyzed phosphorylation of CREB coupled with PKA-SIKs axis-mediated dephosphorylation of CRTCs in α-MSH-induced melanogenic programs, and ii) nuclear import of CRTCs after SIK inhibitor-induced dephosphorylation of CRTCs. Conclusions: Taken together, the targeting phosphorylation circuits on CREB and CRTCs in the expression of MITF-M could be a suitable strategy to prevent pigmentary disorders in the skin.

项与 SIK Inhibitor (Nimbus Therapeutics) 相关的新闻（医药）

2025-04-27

·PipelineReview

Nimbus Therapeutics Announces Initiation of First-in-Human Clinical Trial with NDI-219216, Novel WRN Inhibitor for MSI-H Tumors

– First participants dosed in Phase 1/2 clinical trial – – Preclinical data supporting best-in-class potential of NDI-219216 to be presented at AACR Annual Meeting 2025 – BOSTON, MA, USA I April 25, 2025 I Nimbus Therapeutics, LLC (“Nimbus Therapeutics” or “Nimbus”), a biotechnology company that designs and develops breakthrough medicines through its powerful computational drug discovery engine, today announced that its Phase 1/2 clinical trial of NDI-219216, the company’s investigational non-covalent Werner syndrome helicase (WRN) inhibitor, is actively enrolling and dosing patients with advanced solid tumors. “The initiation of this clinical trial marks an important milestone in advancing our novel WRN inhibitor program,” said Anita Scheuber, M.D., Ph.D., Senior Vice President, Therapeutic Head, Oncology at Nimbus. “We are excited to be evaluating NDI-219216 in patients with advanced disease, who currently have limited treatment options when they experience disease progression on standard of care therapies. The trial is actively enrolling across multiple clinical sites, and we look forward to generating important additional safety and efficacy data as we advance this promising candidate through clinical development.” The Phase 1/2 clinical trial ( NCT06898450 ) is an open-label, dose escalation and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of NDI-219216 in patients with advanced cancer. The study will be conducted in three parts: Part A (dose escalation), Part B (dose optimization), and Part C (dose expansion). Nimbus presented promising preclinical data on NDI-219216 (previously NTX-452) at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in October 2024. The data demonstrate that NDI-219216 is a potent and selective WRN inhibitor with significant tumor regression and sustained complete responses observed at low doses in MSI-H tumor models refractory to immunotherapy and chemotherapy. The company will present new findings comparing covalent versus non-covalent WRN inhibition mechanisms and demonstrating NDI-219216’s superior efficacy across multiple preclinical MSI-H tumor models compared with other clinical-stage WRN inhibitors in a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting being held April 25-30, 2025 in Chicago. The poster entitled “NDI-219216: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors” highlights key preclinical findings related to NDI-219216, including: “The data we are presenting at AACR 2025 highlight several important features of our non-covalent WRN inhibitor,” said Peter J. Tummino, Ph.D., President of Research and Development at Nimbus. “NDI-219216 has the potential for more durable target engagement than covalent inhibitors and maintains potency against potential resistance mutations. Its superior efficacy across multiple MSI-H tumor models, including those less sensitive to other WRN inhibitors and those refractory to current therapies, reinforces our belief that NDI-219216 represents a best-in-class opportunity with broad potential across multiple MSI-H tumor types with significant unmet need.” About NDI-219216 NDI-219216 is a highly potent and selective non-covalent investigational inhibitor of Werner syndrome helicase (WRN) activity being developed for the treatment of MSI-H tumors. WRN is a DNA helicase required for DNA replication and DNA repair and is a validated synthetic lethal target for tumors with microsatellite instability (MSI). MSI is a phenotypic consequence of deficient mismatch repair (dMMR) and occurs in various tumor types, including colorectal, gastric, and endometrial cancers. In preclinical studies, treatment with NDI-219216 exhibited robust antitumor activity across multiple cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) MSI-H tumor models, including models for colorectal, gastric, and endometrial cancers. About Nimbus Therapeutics Nimbus Therapeutics is a clinical-stage, structure-based drug discovery company developing novel small molecule medicines designed to act against well-validated but difficult-to-drug targets implicated in multiple human diseases. The company advances promising research based on a unique strategy that combines leading-edge computational technologies with a tailored array of machine learning-based predictive modeling approaches. Nimbus’ pipeline includes a WRN inhibitor in Phase 1/2 clinical development (NCT06898450) and a diverse portfolio of preclinical programs across oncology, immunology, and metabolism, including a SIK inhibitor program and other undisclosed metabolic targets. The company is headquartered in Boston, Mass. To learn more about Nimbus, please visit www.nimbustx.com . SOURCE: Nimbus Therapeutics

AACR会议免疫疗法

2023-04-05

·BioSpace

iOmx Therapeutics Announces Dosing of First Patient with SIK Inhibitor OMX-0407 in Phase I Clinical Trial

First-in-human trial to test safety and tolerability of a novel immune-protective kinase inhibitor in multiple solid tumors. First iOTarg platform-derived product candidate in the clinic. Martinsried / Munich, Germany, 04 April 2023 - iOmx Therapeutics AG, a biopharmaceutical company developing next-generation targeted cancer immunotherapy treatments, today announced the dosing of the first patient in a Phase I dose escalation study evaluating OMX-0407, a first-in-class oral SIK (salt-inducible kinase) inhibitor. The study is a single-arm, open-label, multicenter, Phase I clinical trial assessing the safety and tolerability of OMX-0407 as monotherapy in patients with previously treated unresectable solid tumors. The clinical trial has been approved by regulators in Spain and Belgium. “With an exciting novel mode of action OMX-0407 holds the potential to address multiple solid tumors that are not responsive to conventional immune checkpoint inhibitors. Our research has shown that inhibition of SIK with OMX-0407 potentiates tumor cell apoptosis by un-leashing intra-tumoral death receptor signaling resulting in anti-tumor efficacy in pre-clinical models resistant to conventional immune checkpoint blockade,” said Dr. Murray Yule, Chief Medical Officer of iOmx. “We would like to express our gratitude to the investigators, their teams and the patient community for their support and trust in our treatment approach with OMX-0407.” Dr. Apollon Papadimitriou, CEO of iOmx added: “We are proud to bring our first iOTarg platform-derived product candidate into the clinic. This is a significant milestone for iOmx as we pursue our goal to deliver better medical options for patients failing current cancer immunotherapy treatments.” SIK family member SIK3 was identified as a novel immune-protective kinase by using iOmx’s systematic screening platform, iOTargTM. Inhibition of SIK3 with OMX-0407 targets a novel immune evasion biology by sensitizing tumors to immune-derived ligands of the TNF superfamily. In preclinical studies OMX-0407 showed strong monotherapy effects reshaping the immune compartment and accelerating tumor cell death. About OMX-0407 OMX-0407 is an oral spectrum-selective salt-inducible kinase (SIK) inhibitor. The SIK family member SIK3 is known for regulating the NF-κB driven gene landscape through phosphorylation of class IIa histone deacetylases (HDACs) and CREB-regulated transcriptional coactivators causing the tumor to evade death receptor-mediated killing. Downregulation of this pathway with OMX-0407 potentiates apoptosis by death receptor ligands, such as tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL) in preclinical studies. About the study The study is a first-in-human, dose-escalation trial of OMX-0407 monotherapy in patients with previously treated unresectable solid tumors. The Phase I trial is designed to characterize the safety, tolerability and pharmacodynamic activity of OMX-0407. The dose escalation scheme is established on the 3+3 design to determine the maximum tolerated dose (MTD). About iOmx Therapeutics iOmx Therapeutics ( ) is a biopharmaceutical company focused on developing first-in-class cancer immuno-therapeutics addressing novel immune checkpoints hijacked by cancer cells. Utilizing its iOTarg™ high-throughput screening platform, iOmx has identified a number of proprietary tumor-associated next-generation immune checkpoints and is advancing a preclinical stage pipeline of promising drug candidates that have the potential to address cancers that are resistant to current immunotherapies. The company’s lead compound OMX-0407 targets SIK, an immune protective kinase family in multiple solid tumors. Founded in 2016 based on the work of its scientific founders Philipp Beckhove, MD, and Nisit Khandelwal, Ph.D., conducted at the German Cancer Research Center, iOmx is backed by international venture capital investors, such as Wellington Partners, Sofinnova Partners and M Ventures as well as MIG Capital and Athos Biopharma. iOmx is based in Martinsried/Munich, Germany. Media contact MC Services AG Katja Arnold, Julia von Hummel, Shaun Brown T: +49(0)89 2102280 iomx@mc-services.eu

临床1期免疫疗法

2023-02-24

·Endpoints

Galapagos goes 0-for-3 on inflammation program as it cuts an early-stage candidate

Galapagos has cut anti-inflammatory drug candidate GLPG4399 following the completion of an early-stage healthy volunteer trial, according to its 2022 annual report released Thursday afternoon. GLPG4399 was a SIK3 inhibitor, one in a line of such salt-inducible kinase (SIK) inhibitors that Galapagos has been trying to develop for inflammatory diseases like rheumatoid arthritis and ulcerative colitis. Originally, the biotech had been planning to move the drug forward in a study with rheumatoid arthritis patients in the middle of this year, but now it’s halting the program and going back to search for new SIK inhibitors. “Medicinal chemistry activities to identify SIK inhibitors with improved pharmacology continues,” Galapagos noted briefly in its press release. GLPG4399 was the third SIK inhibitor Galapagos brought out of the clinic — all part of a franchise Galapagos dubbed Toledo. The first candidate, GLPG3312, similarly only made it through healthy volunteer studies before Galapagos scrapped it. The second, GLPG3970, disappointed in Phase II trials in ulcerative colitis and rheumatoid arthritis, and though it showed some signs of efficacy in psoriasis, Galapagos opted to toss that candidate as well. The small pipeline prune comes after Galapagos laid off 200 staffers and discontinued work on its fibrosis and kidney disease programs, cuts that followed a long string of setbacks at the biotech. In December, Galapagos also announced that its chief business officer André Hoekema and chief medical officer Walid Abi-Saab are retiring, though the latter is remaining with the company until the end of May. Galapagos shares $GLPG fell almost 8% after the markets opened Friday. The biotech did not immediately return request for comment.

临床2期临床失败

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