necuparanib (M 402) / J&J - LARVOL DELTA

Two-pore domain potassium channel TREK-1 contributes to arachidonic acid-induced Ca2+ signaling in human fibroblast-like synovial cells. (PubMed, Biochem Biophys Rep) - "Activation of the TREK-1 channel with 4-(2-Butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB) and ML402 increased this current, and immunocytochemical staining demonstrated TREK-1 expression in hFLSs...In a nominally Ca2+-free medium, spadin had no effect, suggesting that TREK-1 channels regulate plasma membrane Ca2+ influx. Our findings provide the first electrophysiological and pharmacological evidence for the involvement of TREK-1 channels in AA-induced Ca2+ signaling in hFLSs."

Journal • Inflammation • Inflammatory Arthritis

KB-0118, A novel BET bromodomain inhibitor, suppresses Th17-mediated inflammation in inflammatory bowel disease. (PubMed, Biomed Pharmacother) - "Compared to standard BET inhibitors like JQ1 and MS402, KB-0118 exhibited enhanced efficacy in restoring immune balance in IBD, positioning it as a promising therapeutic candidate for chronic inflammatory diseases. Further investigation into KB-0118's specificity and long-term effects will be essential to clarify its full clinical potential."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • BRD4 • IL17A • IL1B • IL23A • STAT3

Structural and Functional Insights into GGCX-FIX Interaction: Implications for Vitamin K-Dependent Bleeding Disorders. (PubMed, bioRxiv) - "Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCX's dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports the hypothesis that GGCX's carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants."

Journal • Hematological Disorders • Osteoporosis • Rheumatology

Quantitative Trait Locus Mapping Combined with RNA Sequencing Identified Candidate Genes for Resistance to Powdery Mildew in Bitter Gourd (Momordica charantia L.). (PubMed, Int J Mol Sci) - "To better understand the genetic basis of powdery mildew resistance in bitter gourd, this study analyzed 300 lines of recombinant inbred lines (RILs) formed by hybridizing the powdery mildew-resistant material MC18 and the powdery mildew-susceptible material MC402...By combining genetic analysis, gene coexpression, and sequence comparison analysis of extreme materials, two candidate genes controlling powdery mildew resistance in bitter gourd were identified (evm.TU.chr3.2934 (C3H) and evm.TU.chr3.2946 (F-box-LRR)). These results represent a step forward in understanding the genetic regulatory network of powdery mildew resistance in bitter gourd and lay a molecular foundation for the genetic improvement in powdery mildew resistance."

Journal

Activation of hTREK-1 by polyunsaturated fatty acids involves direct interaction. (PubMed, Sci Rep) - "PUFAs display the same activation and reversible kinetics than the direct activator ML402 and activate TREK-1 in both whole-cell and inside-out configurations of patch-clamp suggesting that the binding site of PUFAs is accessible from both sides of the membrane, as for ML402. Finally, we proposed a two steps mechanism: first, insertion into the membrane, with no fluidity or curvature modifications at 10 µM, and then interaction with TREK-1 channel to open it."

Journal

CRISPR/Cas9-based Knockout of CFTR Alters Mechano-sensitivity and Proteomic Profile in An Osteocyte Model (ENDO 2023) - "T13-402/17N), and Areas of Excellence Scheme of Hong Kong (AoE/M-402/20)...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*"

Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases

Deficiency of ENaC Excites Pancreatic ß cells to Promote Insulin Secretion (ENDO 2023) - "To our surprise, inhibiting this Na+ channel by selective blockers, amiloride (1-10 µM) or benzamil (1 µM), did not retard insulin secretion, but instead triggered a slow membrane depolarization with electrical bursts (41.5 ± 5.9 mV, measured by patch-clamp, n = 5-6), elicited substantial Ca2+ oscillations (135.2 ± 2.5% of baseline, by Fura-2 imaging, n = 256-380) and promoted insulin secretion (158.2 ± 25.6% of control, by ELISA, t-test, p < 0.05, n = 6) in RINm5F or isolated mouse ß cells...This work was supported in part by National Natural Science Foundation of China (82071599), Areas of Excellence Scheme of Hong Kong (AoE/M-402/20) and Bai Cheng Bai Yuan Start-up Fund (I2022A008).*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The..."

SCNN1A

Introgression of the RppQ gene from field corn improves southern rust resistance in sweet corn. (PubMed, Mol Breed) - "We developed five RppQ-based markers (M0607, M0801, M0903, M3301, and M3402) and employed these markers for foreground selection; 92.3 to 97.9% of the recurrent parent genomes were recovered following three or four rounds of backcrossing...Our study provides an example of successful development of southern rust-resistant sweet corn using a resistance gene from field corn. The online version contains supplementary material available at 10.1007/s11032-022-01315-7."

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Evidence for solanidine as a dietary CYP2D6 biomarker: Significant correlation with risperidone metabolism. (PubMed, Br J Clin Pharmacol) - "The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6."

Biomarker • Journal

Necuparanib combined with nab-paclitaxel + gemcitabine in patients with metastatic pancreatic cancer: Phase 2 results. (ASCO-GI 2017) - P1/2; "No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment."

Clinical • P2 data • Biliary Cancer • Biosimilar • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Venous Thromboembolism

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer. (PubMed, Life (Basel)) - "The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended."

Combination therapy • Journal • Review • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Overexpression of Shinorhizobium meliloti flavohemoglobin improves cell growth and fatty acid biosynthesis in oleaginous fungus Mucor circinelloides. (PubMed, Biotechnol Lett) - "The VHb and SHb genes were integrated into the M. circinelloides MU402 genome by homologous recombination...VHb and SHb expression also increased the proportion of polyunsaturated fatty acids. Overexpressed bacterial hemoglobins, especially SHb, increased cell growth and TFA content in M. circinelloides at low and high aeration, suggesting that SHb improves fatty acid production more effectively than VHb in oleaginous microorganisms."

Journal

The Polysite Pharmacology of TREK K Channels. (PubMed, Adv Exp Med Biol) - "This polysite pharmacology within a relatively small (~70 kDa) ion channel comprises four structurally defined modulator binding sites that occur above (Keystone inhibitor site), at the level of (K modulator pocket), and below (Fenestration and Modulatory lipid sites) the C-type selectivity filter gate that is at the heart of K function. Uncovering this rich structural landscape provides the framework for understanding and developing subtype-selective modulators to probe K function that may provide leads for drugs for anesthesia, pain, arrhythmia, ischemia, and migraine."

Journal • Anesthesia • Atrial Fibrillation • Cardiovascular • CNS Disorders • Migraine • Pain

Heparanase Inhibitors in Cancer Progression: Recent Advances. (PubMed, Curr Pharm Des) - "HPIns can be a better target to be explored against various cancers."

Journal • Immunology • Inflammation • Oncology

Randomised phase II trial of gemcitabine and nab-paclitaxel with necuparanib or placebo in untreated metastatic pancreas ductal adenocarcinoma. (PubMed, Eur J Cancer) - P1/2 | "The addition of necuparanib to standard of care treatment for advanced PDAC did not improve OS. Safety was acceptable. No further development of necuparanib is planned although targeting the coagulation cascade pathway remains relevant in PDAC. NCT01621243."

Clinical • Journal • P2 data • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Meet the Professor Seminar. MP402. CYSTIC FIBROSIS THERAPEUTICS: GREAT STRIDES AND FUTURE DIRECTIONS (ATS 2020) - "Gene therapy and gene/editing development status updates for the last 10% of pwCF with more difficult to treat mutations will also be discussed. Demonstrate improved understanding of the importance of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Apply knowledge of CFTR genetics to integrate new treatment options for people with CF Define potential new strategies to manage the care of people with CF."

CFTR

Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4. (PubMed, Proteins) - "The unbinding pathways of MS402 from BD1 and BD2 pockets are also different. We expect that these findings will be helpful for novel inhibitor design and rational structural modification of existing inhibitors to increase their BD1-selectivity."

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Necuparanib, a multi-targeting heparan sulfate mimetic, targets tumor and stromal compartments in pancreatic cancer. (PubMed, Mol Cancer Ther) - "Finally, we confirmed necuparanib's in vivo activity by analyzing plasma samples of patients enrolled in a Phase I/II study in patients with metastatic pancreatic cancer; treatment with necuparanib plus standard of care significantly increased TIMP3 plasma protein levels. Together, these results demonstrate necuparanib acts as a broad multi-targeting therapeutic with in vitro and in vivo anti-invasive and anti-metastatic activity."

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