Last update 01 Nov 2024

NEK7

Last update 01 Nov 2024

Basic Info

Synonyms

NEK7, Never in mitosis A-related kinase 7, NIMA (never in mitosis gene a)-related kinase 7

+ [3]

Introduction

Protein kinase which plays an important role in mitotic cell cycle progression (PubMed:17101132, PubMed:31409757, PubMed:19941817). Required for microtubule nucleation activity of the centrosome, robust mitotic spindle formation and cytokinesis (PubMed:17586473, PubMed:19414596, PubMed:31409757, PubMed:19941817, PubMed:26522158). Phosphorylates EML4 at 'Ser-146', promoting its dissociation from microtubules during mitosis which is required for efficient chromosome congression (PubMed:31409757). Phosphorylates RPS6KB1 (By similarity). Acts as an essential activator of the NLRP3 inflammasome assembly independently of its kinase activity (PubMed:26642356, PubMed:36442502). Acts by unlocking NLRP3 following NLRP3 tranlocation into the microtubule organizing center (MTOC), relieving NLRP3 autoinhibition and promoting formation of the NLRP3:PYCARD complex, and activation of CASP1 (PubMed:26642356, PubMed:31189953, PubMed:36442502). Serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division: interaction with NEK9 prevents interaction with NLRP3 and activation of the inflammasome during mitosis (PubMed:26642356, PubMed:31189953).

Drugs associated with NEK7

Ofirnoflast

Target

NEK7 x NLRP3

Mechanism

NEK7 inhibitors [+1]

Active Org.

Halia Therapeutics, Inc.Startup

Originator Org.

Halia Therapeutics, Inc.Startup

Active Indication

Inflammation [+4]

Inactive Indication-

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CPT-6281

Target

GSPT1 x NEK7 x SALL4

Mechanism

GSPT1 modulators [+3]

Active Org.

Captor Therapeutics SA

Originator Org.

Captor Therapeutics SA

Active Indication

Hepatocellular Carcinoma

Inactive Indication-

Drug Highest PhaseIND Application

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

HT-6283

Target

NEK7

Mechanism

NEK7 inhibitors

Active Org.

Halia Therapeutics, Inc.Startup

Originator Org.

Halia Therapeutics, Inc.Startup

Active Indication

Neuroinflammation

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with NEK7

NCT06241742 / CompletedPhase 2

A Phase-2 Study to Evaluate the Ability of HT-6184 to Attenuate Diagnostic Biomarkers of Post-procedure Acute Inflammation and Manage Pain Following Third Molar Extraction

The goal of this clinical trial is to test the ability of HT-6184 to decrease inflammation and pain in patients after third molar removal.
The main question it aims to answer are:
* Does HT-6184 decrease inflammation in patients after third molar removal?
* Does HT-6184 decrease pain in patients after third molar removal?
Participants will be asked to do the following during the clinical trial:
* Take a single oral dose of HT-6184 or placebo
* Allow a oral surgeon remove their third molar teeth
* Blood draws on 5 occurrences
* Rate their pain intensity
* Attend two follow-up appointments on day 1 and day 2 after third molar removal
* Participate in one follow-up phone call 5-7 days after third molar removal

Start Date12 Feb 2024

Sponsor / Collaborator

Halia Therapeutics, Inc.Startup

CTRI/2023/11/059758 / Not yet recruitingPhase 2

A Phase 2a study of HT-6184 in subjects with IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndrome (MDS) and Symptomatic Anemia. - NIL

Start Date24 Nov 2023

Sponsor / Collaborator

Halia Therapeutics, Inc.Startup

NCT05447546 / CompletedPhase 1

A Phase 1, Single-Center, Randomized, Placebo-controlled, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of HT-6184 in Healthy Human Subjects

The primary objectives of this study are to evaluate the safety and tolerability of HT-6184 when administered as single oral doses at escalating dose levels in healthy volunteer subjects.
The secondary objectives of this study are to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of HT-6184. Results of the PD analyses will be used to determine the minimal biologically effective dose (MBED): the lowest dose that achieves >70% target inhibition compared to unstimulated vehicle controls over 24 hours in 4 of 6 treated volunteers.

Start Date15 Jun 2022

Sponsor / Collaborator

Halia Therapeutics, Inc.Startup

[+1]

100 Clinical Results associated with NEK7

100 Translational Medicine associated with NEK7

0 Patents (Medical) associated with NEK7

278

Literatures (Medical) associated with NEK7

01 Feb 2025·Current Neuropharmacology

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome

Article

Author: Alboni, Silvia ; Benatti, Cristina ; Rigillo, Giovanna ; Brunello, Nicoletta ; Pani, Luca ; Blom, Johanna M.C. ; Tascedda, Fabio ; Ciani, Miriam

Background:Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. The potential link between VTX and NLRP3, along with other inflammasomes, remains un-explored.Methods:The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD.Results:Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was demonstrated that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway.Conclusion:Thus, a novel VTX molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.

31 Dec 2024·Autoimmunity

OGT-induced O-GlcNAcylation of NEK7 protein aggravates osteoarthritis progression by enhancing NEK7/NLRP3 axis

Article

Author: Yang, Yadong ; Zeng, Zhaogan ; Liu, Sheng ; He, Chunlei ; Wu, Qiang ; He, Huabin ; Hu, Meiyu

BACKGROUNDSThe role of O-GlcNAc transferase (OGT)-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) has been reported in multiple human diseases. However, its specific functions in osteoarthritis (OA) progression remain undetermined.OBJECTIVEThis study focused on the target proteins of OGT-induced O-GlcNAcylation in OA and the specific functional mechanism.METHODSThe levels of total O-GlcNAc and OGT were measured in both in vitro and in vivo OA models using western blot. The effects of OGT knockout on OA progression were detected through Safranin O staining, immunohistochemical staining and OARSI score evaluation. The effects of OGT silencing on LPS-induced chondrocyte injury were assessed by performing loss-of function assays. Co-immunoprecipitation (co-IP) was conducted to verify the effect of OGT-induced O-GlcNAcylation on the interaction between NEK7 and NLRP3. The role of OGT in modulating the O-GlcNAcylation and phosphorylation levels of NEK7 was analysed using western blot.RESULTSThe OGT-indued O-GlcNAcylation level was increased in both in vitro and in vivo OA models. Knockout of OGT mitigated OA progression in model mice. Additionally, silencing of OGT suppressed LPS-induced chondrocyte pyroptosis. Moreover, silencing of OGT inhibited the O-GlcNAcylation and enhanced the phosphorylation of NEK7 at S260 site, thereby blocking the binding of NEK7 with NLRP3.CONCLUSIONOGT-induced NEK7 O-GlcNAcylation promotes OA progression by promoting chondrocyte pyroptosis via the suppressing interaction between NEK7 and NLRP3.

01 Nov 2024·International Immunopharmacology

NINJ1: A new player in multiple sclerosis pathogenesis and potential therapeutic target

Review

Author: Zhou, Shengjun ; Huang, Yi ; Wei, Liangzhe ; Chen, Siqi ; Zhang, Enhao ; Xu, Yinbin ; Dai, Zifeng

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest a potential role for nerve injury-induced protein 1 (NINJ1) in MS pathogenesis. NINJ1, a protein involved in cell death and inflammation, may contribute to the infiltration and activation of inflammatory cells in the CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during cell death, leading to the release of inflammatory mediators and further tissue damage. This review explores the emerging evidence for NINJ1's involvement in MS. It discusses how NINJ1 might mediate the migration of immune cells across the blood-brain barrier, exacerbate neuroinflammation, and participate in plasma membrane rupture-related damage. Finally, the review examines potential therapeutic strategies targeting NINJ1 for improved MS management. Abbreviations: MS, Multiple sclerosis; CNS, Central nervous system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma membrane rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated molecular patterns; PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis factor; APCs, Antigen-presenting cells; ECs, Endothelial cells; TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear cells; FACS, Fluorescence-activated cell sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T cell receptor; ROS, Reactive oxygen species; AP-1, Activator protein-1; ANG1, Angiopoietin 1; BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related protein 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase 1; PAK1, p21-activated kinases 1; Rac1, Ras-related C3 botulinum toxin substrate 1; β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TLR4, Toll-like receptor 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor associated factor 6; TAB2/3, TAK1 binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; JNK, c-Jun N-terminal kinase; ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; AP-1, activator protein-1; ASC, Apoptosis-associated Speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NLRP3, Pyrin domain-containing 3; CREB, cAMP response element-binding protein.

News (Medical) associated with NEK7

28 Oct 2024

·www.biopharmadive.com

Monte Rosa joins with Novartis in ‘molecular glue’ drug deal

Dive Brief:Novartis will pay $150 million to gain rights to molecular glue degraders being developed by biotechnology company Monte Rosa Therapeutics to target an immune signaling protein, known as VAV1, that has long been considered undruggable.The deal, announced by the companies Monday morning, could yield up to $2.1 billion in further payments by Novartis to Monte Rosa should the licensed research reach certain development, regulatory and sales milestones.Molecular glue degraders are small molecule drugs that join together a target protein with an enzyme responsible for flagging cellular detritus for disposal. In Monte Rosas case, the company believes degrading VAV1 could weaken certain immune cell functions, thereby slowing the progression of immune-mediated diseases.Dive Insight:Novartis deal with Monte Rosa centers on an early-stage drug candidate dubbed MRT-6160 thats currently in a Phase 1 study of healthy volunteers.Monte Rosa and Novartis see potential for MRT-6160 to treat multiple systemic and neurological autoimmune diseases, Monte Rosa CEO Markus Warmuth said in an email to BioPharma Dive.Under the deal, Monte Rosa will wrap up the ongoing Phase 1 clinical study, while Novartis will handle development from Phase 2 onwards. The biotech will co-fund any Phase 3 testing that occurs and also share in any profits or losses associated with MRT-6160s commercialization, should it get that far.“Novartis has had a long-standing interest in molecular glue degraders, which offer the potential to tackle challenging biological targets, said Fiona Marshall, head of biomedical research at Novartis, in the companies statement. We are excited about their application in immunology and the early progress we have seen by Monte Rosa in this space and with MRT-6160.For Monte Rosa, Novartis support will help it fully explore the potential of MRT-6160 in a variety of immune diseases, Warmuth said in his email. The company plans to use the $150 million it will receive from Novartis to extend its operating runway and advance its own research.In addition to VAV1, Monte Rosa is exploring targeting other proteins, including ones called NEK7, CDK2 and CCNE1, with its molecular glue technology.Monte Rosa previously partnered with Novartis cross-town rival Roche to apply molecular glue degraders to cancer and neurological diseases. Other biotechs are exploring the drug concept as well, and have struck collaborations with Pfizer, Astellas and Bristol Myers Squibb. '

Phase 1PROTACs

21 Oct 2024

·www.prnewswire.com

Halia Therapeutics to Attend Global Health Exhibition 2024

Halia Therapeutics will showcase its LRRK2 and NEK7 inhibitors targeting Alzheimer's disease and obesity. LEHI, Utah, Oct. 21, 2024 /PRNewswire/ -- Halia Therapeutics, Inc. (Halia), a clinical-stage biopharmaceutical company pioneering innovative treatments for inflammatory and neurodegenerative diseases, today announced that it will showcase its scientific data and progressive pipeline at the upcoming Global Health Exhibition. The event will occur October 21–23, 2024, in Riyadh, Saudi Arabia. Halia Therapeutics will host an exhibition booth to showcase its efforts in targeting two indications, Alzheimer's disease and obesity. Halia's candidate HT-4253 is a LRRK2 inhibitor administered orally with excellent brain penetration. LRRK2 is a key modulator of neuroinflammation, which plays a critical role in neurodegenerative diseases. HT-6184 is a first-in-class, selective and orally bioavailable inhibitor of the NEK7/NLRP3 inflammasome. HT-6184 is being tested in combination with semaglutide to target inflammation, which has been linked to obesity-related metabolic dysfunction. Halia's drug candidates are designed to provide novel approaches to improve patients' lives affected by neurodegenerative diseases and chronic inflammatory disorders. Global Health Exhibition unites visionaries, policymakers, government agencies, healthcare luminaries, scientists and futurists to forge a healthier, more innovative future. Visit Halia at booth H1C-W83 in the USA Pavillion. To view the full agenda please visit About NLRP3 NLRP3, an innate immune sensor, is activated in response to various pathogenic and sterile stimuli. Activation of NLRP3 triggers the release of the pro-inflammatory cytokines IL-1β and IL-18 and induces a lytic cell death process called pyroptosis. These mechanisms lead to systemic chronic inflammation. Halia's therapeutic inhibits NLRP3, preventing the formation of the NLRP3 inflammasome and promoting its disassembly once formed. This inhibition blocks the production and release of IL-1β and IL-18. Chronic NLRP3 inflammasome activation is believed to drive the onset and progression of many conditions, including fibrotic, dermatological, and auto-inflammatory diseases. Moreover, it plays a significant role in neurodegenerative and neuroinflammatory disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. About HT-6184 HT-6184 is a groundbreaking drug candidate that targets the protein NEK7 through an allosteric mechanism. NEK7 plays a crucial role in the NLRP3 inflammasome, which is essential for its assembly and activity maintenance. In preclinical models, Halia demonstrated that inhibiting the NEK7's ability to bind to NLRP3 disrupts inflammasome signaling and reduces the inflammatory response. HT-6184 not only prevents the formation of the NLRP3 inflammasome but also promotes its disassembly once activated. (Halia unpublished data). About HT-4253 HT-4253 is an orally administered small molecule with excellent brain penetration that targets LRRK2, a key mediator of neuroinflammation. Chronic brain inflammation is a driver of several neurodegenerative diseases, including Parkinson's and Alzheimer's. Halia scientists have demonstrated that LRRK2's essential role in regulating neuroinflammation. LRRK2 inhibition by HT-4253 offers a novel approach to treat neurodegenerative diseases with an inflammation component, potentially altering disease progression. HT-4253 is undergoing a Phase I trial to evaluate the safety and tolerability in healthy volunteers (NCT06537817). About Halia Therapeutics, Inc. Halia Therapeutics is pioneering novel therapeutics to enhance patients' lives with chronic inflammatory disorders and neurodegenerative diseases. Halia's initial programs target NEK7 and LRRK2.Headquartered in Lehi, Utah, Halia Therapeutics invites you to learn more about our work. Visit our website at , connect with us on LinkedIn, and follow our updates on Twitter (X). Company Contact Halia Therapeutics [email protected] +1 (385) 355-4315 Media Contact: Ignacio Guerrero-Ros, Ph.D. Russo Partners, LLC +1 (646) 942-5604 [email protected] SOURCE Halia Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 1

14 Oct 2024

·www.prnewswire.com

Halia Therapeutics to Participate in Panel at BIO Investor Forum 2024

Dr. David J. Bearss, CEO, will partake in a panel focused on Neurodegenerative Disease Targets and Pipelines on Tuesday, October 15 at 11:00-11:50 am PT LEHI, Utah, Oct. 14, 2024 /PRNewswire/ -- Halia Therapeutics, Inc. (Halia), a clinical-stage biopharmaceutical company at the forefront of developing innovative treatments for inflammatory and neurodegenerative diseases, today announced that David J. Bearss, Ph.D., President and CEO of Halia Therapeutics, will participate in a panel at the BIO Investor Forum taking place October 15-16, 2024, in San Francisco, CA. Dr. Bearss will take part in the panel discussion: 'Expansion of Neurodegenerative Disease Targets and Pipelines' which will take place on Tuesday, October 15, 11:00-11:50 am PT at the Venetian Room, Fairmont San Francisco. This session will feature leading innovators who will discuss the latest advancements in diverse approaches to neurodegenerative diseases. Attendees will learn about the evolving landscape of neurodegenerative disease research and development, the potential of novel targets, and the implications for future treatment and investment opportunities. A Phase 1 trial evaluating Halia Therapeutics' compound HT-4253 was recently initiated to assess its safety, tolerability, and pharmacokinetics in healthy adults. HT4253 functions by inhibiting LRRK2, a regulator in neuroinflammation associated with Alzheimer's and Parkinson's disease. Bio Investor Forum showcases drug development programs that are ready for partnering and venture funding, with a focus on treating patients by accelerating the progress of new therapeutic technologies into commercialization. David J. Bearss, Ph.D., President and CEO, will be available for one-on-one investor meetings with registered conference attendees at the forum. Meetings can be scheduled through the partnering system. To view the full agenda please visit . About HT-4253 HT-4253 is an orally administered small molecule with excellent brain penetration that targets a mediator of neuroinflammation called LRRK2. Chronic inflammation in the brain is a driver of several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. Halia scientists have shown that LRRK2 is an essential regulator of neuroinflammation. LRRK2 inhibition by HT-4253 could represent a new way to treat neurodegenerative diseases with an inflammation component by changing how the disease progresses. HT-4253 is currently being evaluated in a Phase I trial determining its safety and tolerability in healthy volunteer subjects (NCT06537817). About Halia Therapeutics, Inc. Halia Therapeutics is discovering and developing a pipeline of novel therapeutics to improve patients' lives with chronic inflammatory disorders and neurodegenerative diseases, with its initial programs targeting NEK7 and LRRK2. Halia's lead candidate, HT-6184, a novel NEK7/NLRP3 inhibitor, has completed a Phase I study (NCT05447546) evaluating the safety and tolerability of HT-6184 when administered as single or multiple oral doses at escalating dose levels in healthy volunteer subjects. Halia has also initiated 2 Phase II trials to evaluate the efficacy of HT-6184 for the treatment of lower-risk myelodysplastic syndromes (LR-MDS) and on post-procedure diagnostic biomarkers of inflammation and pain (NCT06241742). Halia recently initiated a Phase I trial evaluating the safety and tolerability of its LRRK2 inhibitor, HT-4253, in healthy volunteer subjects (NCT06537817). The company's headquarters are in Lehi, Utah. For more information, visit or follow us on LinkedIn and Twitter (X). Company Contact Halia Therapeutics [email protected] +1 (385) 355-4315 Media Contact: Ignacio Guerrero-Ros, Ph.D. Russo Partners, LLC +1 (646) 942-5604 [email protected] SOURCE Halia Therapeutics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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