K-161 / Kowa - LARVOL DELTA

Tripartite Motif Containing 65 Deficiency Confers Protection Against Acute Kidney Injury via Alleviating Voltage-Dependent Anion Channel 1-Mediated Mitochondrial Dysfunction. (PubMed, MedComm (2020)) - "Moreover, the knockout of the Trim65 gene in mice exhibited a substantial protective impact against rhabdomyolysis, ischemia-reperfusion (I/R), and cisplatin-induced AKI. Mechanistically, TRIM65 directly binds and mediates K48/K63-linked polyubiquitination modifications of voltage-dependent anion channel 1 (VDAC1) at its K161 and K200 amino acid sites...Conversely, the overexpression of VDAC1 in renal tissues has been demonstrated to negate the protective effect of TRIM65 deficiency on AKI. These findings suggest that TRIM65 may play a role regulating of AKI through the targeting of VDAC1-dependent mitochondrial function, offering potential avenues for the development of new drug targets and strategies for the treatment of AKI."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Reperfusion Injury • Targeted Protein Degradation • VDAC1

The impact of blood flow restriction training combined with low-load resistance training on the risk of falls in patients with knee osteoarthritis in China: a single-centre, two-arm, single-blind, parallel randomised controlled trial protocol. (PubMed, BMJ Open) - P=N/A | "This study has been approved by the Ethics Review Committee of the First Hospital of Quanzhou Affiliated Fujian Medical University (2024-K161). The results of the study will be disseminated through peer-reviewed publications. ChiCTR2400087829."

Clinical • Clinical protocol • Journal • Immunology • Musculoskeletal Diseases • Osteoarthritis • Pain • Rheumatology

Urinary Acetylated Albumin as a Biomarker of Nephritis in Patients with Systemic Lupus Erythematosus (ACR Convergence 2024) - "This was followed by multiple reaction monitoring (MRM) analysis in 25 healthy subjects, 29 SLE patients, 32 newly diagnosed LN patients, and 16 treated LN patients to validate the findings.Stable isotope-labeled internal standard (SIS) peptides for five acetylated peptides (albumin at K36, K161, and K402; serotransferrin at K588; and C11orf40 at K45) were synthesized... Acetylated albumin at K402 is a novel potential urine biomarker for detecting renal damage in patients with newly diagnosed lupus nephritis. Figure 1. Receiver Operating Characteristic Curve of Acetylated Albumin at K402 for Newly Diagnosed Lupus Nephritis"

Biomarker • Clinical • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus

Artemisinin Enhances Anti-Tumor Immunity by Increasing FGL1 Ubiquitination Degradation via Activating TRIM21 In NSCLC (IASLC-WCLC 2024) - "Tumors were enlarged after overexpression of FGL1 and could be shrunk after overexpression of TRIM21, but not after mutation of K161...Conclusions : Artemisinin can increase TRIM21 expression, thereby enhancing FGL1 ubiquitination degradation and activating anti-tumor immunity. Artemisinin combined with immunotherapy may improve therapeutic efficacy and provide a new target for immunotherapy in NSCLC."

IO biomarker • Infectious Disease • Lung Cancer • Malaria • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD8 • FGL1 • LAG3 • TRIM21

Structural insights into the disulfide isomerase and chaperone activity of TrbB of the F plasmid type IV secretion system. (PubMed, Curr Res Struct Biol) - "Residues W37-K161, which include the active thioredoxin motif, are sufficient for DI activity...Lastly, size exclusion chromatography analysis of TrbBWT in the presence of TraW, a T4SSF assembly protein predicted to interact with TrbBWT, does not support the inference of a stable complex forming in vitro. This work advances our understanding of TrbB's structure and function, explores the role of structural disorder in protein dynamics in the context of a T4SSF accessory protein, and highlights the importance of redox-assisted protein folding in the T4SSF."

Journal • Infectious Disease

Effects of Glycosylation Combined with Phosphate Treatment on the Allergenicity and Structure of Tropomyosin in Litopenaeus vannamei. (PubMed, J Agric Food Chem) - "Meanwhile, the α-helix content reduced, surface hydrophobicity increased, and 10 specific amino acids (K30, K38, S39, K48, K66, K74, K128, K161, S210, and K251) were modified by glycosylation on six IgE linear epitopes of GOS-SP-TM. In the BALB/c mice allergy model, GOS-SP-TM could significantly reduce the levels of specific IgE, IgG1, and CD4+IL-4+, while the levels of IgG2a, CD4+CD25+Foxp3+, and CD4+IFN-γ+ were increased, which equilibrated Th1 and Th2 cells, thus alleviating allergic symptoms. These results indicated that glycosylation combined with phosphate treatment can provide a new insight into developing hypoallergenic shrimp food."

Journal • Allergy • Immunology • CD4 • FOXP3 • IFNG • IL2RA • IL4 • ISG20

Astragaloside IV inhibits cell viability and glycolysis of hepatocellular carcinoma by regulating KAT2A-mediated succinylation of PGAM1. (PubMed, BMC Cancer) - "AS-IV inhibited cell viability and glycolysis in HCC by regulating KAT2A-mediated succinylation of PGAM1, suggesting that AS-IV might be a potential and suitable therapeutic agent for treating HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • PGAM1

The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases. (PubMed, Int J Mol Sci) - "The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes."

Journal • Review • Allergy • Alzheimer's Disease • Cardiovascular • CNS Disorders • Hematological Malignancies • Immunology • Leukemia • Metabolic Disorders • Oncology

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice. (PubMed, Arterioscler Thromb Vasc Biol) - "By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF...Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Hypertension • Immunology • HIF1A • SIRT3

A Study to Confirm the Efficacy and Safety of K-161 Ophthalmic Solution for Treatment of Moderate to Severe Dry Eye Disease (clinicaltrials.gov) - P3 | N=644 | Completed | Sponsor: Kowa Research Institute, Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jul 2024 ➔ Dec 2023

Trial completion • Trial completion date • Dry Eye Disease • Ophthalmology

Preparation and epitope mapping of monoclonal antibodies against African swine fever virus p22 protein. (PubMed, Int J Biol Macromol) - "Our results showed that amino acids C39, K40, V41, D42, C45, G48, E49, and C51 directly bound to 14G1, while the key amino acid epitope for 22D8 included K161, Y162, G163, D165, H166, I167, and I168. Homologous and structural analysis revealed that these sites were highly conserved across Asian and European ASFV strains, and the amino acids identified were located on the surface of p22. Thus, our study contributes to a better understanding of the antigenicity of the ASFV p22 protein, and the results could facilitate the prevention and control of ASF."

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Functional Coupling of ANXA1 and KCa3.1 Attenuated Renal Tubulointerstitial Fibrosis in Diabetic Kidney Disease (KIDNEY WEEK 2023) - "SUMOylation sites were predicted by SUMOsp2.0, and ANXA1 lysine residues K113, K161, K185, K257 and K312 were mutated to test the relative site change. Our study suggests that ANXA1-KCa3.1 functional coupling may be a promising therapeutic strategy to mitigate DKD-induced TIF."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • ANXA1 • FN1 • KCNN4 • TGFB1

A Study to Confirm the Efficacy and Safety of K-161 Ophthalmic Solution for Treatment of Moderate to Severe Dry Eye Disease (clinicaltrials.gov) - P3 | N=620 | Active, not recruiting | Sponsor: Kowa Research Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Dry Eye Disease • Ophthalmology

Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk. (PubMed, Biochemistry) - "Furthermore, two of the mutated residues (Ack1 A156 and K161) critical for catalytic activity are highly conserved among other TKs, and their substitution in other members of the kinase family could have implications in cancer. In contrast to canonical gain-of-function mutations in TKs observed in many cancers, we report loss-of-function mutations in Ack1 and Brk, highlighting the complexity of TK involvement in human diseases."

Journal • Cardiovascular • CNS Disorders • Developmental Disorders • Immunology • Inflammatory Arthritis • Lupus • Oncology • Psychiatry • Systemic Lupus Erythematosus

A Study to Confirm the Efficacy and Safety of K-161 Ophthalmic Solution for Treatment of Moderate to Severe Dry Eye Disease (clinicaltrials.gov) - P3 | N=620 | Recruiting | Sponsor: Kowa Research Institute, Inc. | Trial completion date: Oct 2023 ➔ Jul 2024 | Trial primary completion date: Dec 2022 ➔ Sep 2023

Trial completion date • Trial primary completion date • Dry Eye Disease • Ophthalmology

Murine double minute 2 aggravates adipose tissue dysfunction through ubiquitin-mediated six-transmembrane epithelial antigen of prostate 4 degradation. (PubMed, iScience) - "Thereinto, the K18 and K161 sites of STEAP4 were ubiquitin-modificated by MDM2. Finally, STEAP4 restoration in eWAT of Mdm2-AKI mice on a HFD rescued MDM2-induced adipose dysfunction, insulin resistance, and hepatic steatosis. Summary, the MDM2-STEAP4 axis in eWAT plays an important role in maintaining healthy adipose tissue function and improving hepatic steatosis."

Journal • Preclinical • Immunology • Inflammation • Targeted Protein Degradation • MDM2 • STEAP4

ARIH2 regulates the proliferation, DNA damage and chemosensitivity of gastric cancer cells by reducing the stability of p21 via ubiquitination. (PubMed, Cell Death Dis) - "Further mechanistic investigations revealed that ARIH2 interacts with p21 and induces p21 ubiquitination, and that the K48 residue of ubiquitin and the K161 residue of p21 play key roles in ARIH2-mediated p21 ubiquitination...In addition, ARIH2 knockdown induced DNA damage, and then induced cell apoptosis and regulated the chemosensitivity of gastric cancer cells after combined treatment with 5-fluorouracil. Generally, our results indicated that ARIH2 promotes the proliferation of gastric cancer cells and regulates p21 expression. These data demonstrate the need to further evaluate the potential therapeutic implications of ARIH2 in gastric cancer."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDKN1A

A Study to Confirm the Efficacy and Safety of K-161 Ophthalmic Solution for Treatment of Moderate to Severe Dry Eye Disease (clinicaltrials.gov) - P3 | N=620 | Recruiting | Sponsor: Kowa Research Institute, Inc.

New P3 trial • Dry Eye Disease • Ophthalmology

SHIP-2 inhibits human microglia-like cell function in a TREM2 independent manner (IMMUNOLOGY 2022) - "Treatment with a pan SHIP-1/ 2 inhibitor (SHIPi) K161 significantly improved the phagocytic uptake of fluorescently tagged oligomerized Aβ42 in both HMC3WT and HMC3T2KO...Further studies to look for SHIP2-TREM2 interactions and the effect of SHIP-1 expression in combination with SHIPi treatment in HMC3 cell function are underway. SHIPi are non-toxic in HCM3 cells and may offer potential treatment options for AD."

Alzheimer's Disease • CNS Disorders • CSF1 • INPP5D

[VIRTUAL] SHIP-1 Inhibitors improve human microglial-like cell function (IMMUNOLOGY 2021) - "To test this hypothesis, we treated human microglial like (HMC3) cells, expressing endogenous TREM2, SHIP-1, Iba-1, and CD68, with small molecule inhibitors of SHIP-1 (SHIPi) (3AC) and its paralog SHIP-2 (K161)...Further studies are underway to determine the effect of SHIPi on metabolic fitness. SHIPi are safe and effective in mouse models of metabolic dysfunction and obesity and could be an ideal treatment for AD alone or in combination with stimulating TREM2 antibodies."

Alzheimer's Disease • CNS Disorders • Genetic Disorders • Metabolic Disorders • Obesity • CD68 • INPP5D

Kinetic, spectral, and structural studies of the slow-binding inhibition of the Escherichia coli dihydrodipicolinate synthase by 2, 4-oxo-pentanoic acid. (PubMed, Arch Biochem Biophys) - "The spectra of the enzyme in the presence of pyruvate and acetopyruvate shows the initial formation of the pyruvate enamine intermediate followed by the slower appearance of the E:acetopyruvate spectra with a rate constant of about 0.013 s. The spectral studies suggest the formation of a Schiff base between acetopyruvate and K161 on enzyme that subsequently deprotonates to form a resonance stabilized anion similar to the enamine intermediate formed with pyruvate. The crystal structure of the E:acetopyruvate complex confirms the formation of the Schiff base between acetopyruvate and K161."

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A Study Assessing the Safety, Efficacy, and Optimum Dosage of K-161 in Subjects With Moderate to Severe Dry Eye Disease (clinicaltrials.gov) - P2; N=238; Completed; Sponsor: Kowa Research Institute, Inc.; Recruiting ➔ Completed

Clinical • Trial completion

Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. (PubMed, J Cell Sci) - "We find that highly potent pan-SHIP1/2 inhibitors can significantly increase lysosomal compartment size and phagocytosis of dead neurons and Aβ1-42 by microglia in vitro We show that one of the more potent and water-soluble pan-SHIP1/2 inhibitors, K161, can penetrate the blood-brain barrier and consistent with this K161 increases the capacity of CNS-resident microglia to phagocytose beta-amyloid and apoptotic neurons following systemic administration. These findings provide the first demonstration that small molecule modulation of microglia function in vivo is feasible and suggest the possibility that dual inhibition of the SHIP1 and 2 paralogs could provide a novel means to enhance basal microglial homeostatic functions for therapeutic purposes in Alzheimer's Disease, and possibly other dementias where increased microglial function could be beneficial."

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