SAL-003 (evolocumab biosimilar) / Shenzhen Salubris, Ligand - LARVOL DELTA

Blocking PCSK9 suppresses hepatocellular carcinoma immune escape by decreasing FLI1-mediated SPP1 and PD-L1 expression. (PubMed, J Immunother Cancer) - "PCSK9 promoted HCC immune escape by upregulating SPP1 and PD-L1 via NOTCH3/FLI1 signaling. CRISPR ABE-mediated PCSK9 deficiency and PCSK9 inhibitor parecoxib may serve as effective strategies to inhibit HCC."

IO biomarker • Journal • Hematological Malignancies • Hepatocellular Cancer • Leukemia • Oncology • Solid Tumor • CD8 • FLI1 • NOTCH3 • PCSK9 • PD-L1 • SPP1

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Study to Evaluate the Safety and Efficacy of SAL003 in Combination With Statin Therapy in Patients With Hypercholesterolemia and Mixed Dyslipidemia (clinicaltrials.gov) - P3 | N=720 | Completed | Sponsor: Shenzhen Salubris Pharmaceuticals Co., Ltd.

New P3 trial • Dyslipidemia • Metabolic Disorders • Mixed Hyperlipidemia

Allosteric inhibition of the PCSK9-LDLR interaction: structural insights for small molecule design. (PubMed, Phys Chem Chem Phys) - "MI-based dynamic mapping shows that potent inhibitors preserve long-range coupling between the allosteric pocket and the LDLR-binding segment D374-C378, whereas weak inhibitors fail to maintain this communication pathway, similar to the inhibitor-free form. Together, these results define a structural dynamic axis that links localized interfacial modulation to long-range allosteric communication and provide a mechanistic framework for the design of next-generation allosteric PCSK9 inhibitors with enhanced potency and efficacy."

Journal

Whole exome sequencing identifies concurrent LDLR and ABCG8 mutations in a Saudi family with familial hypercholesterolemia and Sitosterolaemia. (PubMed, Front Genet) - "The proband responded remarkably to ezetimibe monotherapy, while his children required combination therapy with high-intensity rosuvastatin and PCSK9 inhibitor Evolocumab for LDL-C reduction. This study presents the first extensive molecular characterization of a dual FH-sitosterolemia phenotype. It emphasizes the critical role of genomic diagnostics in managing complex lipid disorders and supports personalized medicine approaches, especially in consanguineous populations where blended phenotypes may be underrecognized."

Journal • Diabetes • Dyslipidemia • Endocrine Disorders • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • LDLR

The Effects of Inclisiran on the Subclinical Inflammatory Markers of Atherosclerotic Cardiovascular Disease in Patients at High Cardiovascular Risk. (PubMed, Pharmaceuticals (Basel)) - "To date, data on the potential impact of PCSK9 inhibitors, especially inclisiran, on the course of inflammation is still lacking. This study confirmed the ability of inclisiran to reduce LDL-c levels in patients at high cardiovascular risk just after one dose of the drug. Furthermore, it appeared that beyond its lipid-lowering effect, the drug may also affect some inflammatory processes involved in the initiation and progression of atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Heterozygous Familial Hypercholesterolemia • Inflammation • Metabolic Disorders • CD40LG • IL18 • PTX3

Saffron and its active constituents ameliorate hypercholesterolemia by inhibiting PCSK9 and modulating Sortilin, LDLR, and SREBP-2 signaling in high fat diet induced hypercholesterolemic C57BL/6 mice. (PubMed, J Ethnopharmacol) - "Saffron and its active components (CN and CR) are novel natural PCSK9 inhibitors that effectively ameliorate hypercholesterolemia by modulating sortilin, LDLR and SREBP-2 pathway, potentially opening the way for developing new therapeutic approaches for managing cholesterol related disorders."

Journal • Preclinical • Dyslipidemia • Genetic Disorders • Hepatology • Inflammation • Metabolic Disorders • Obesity • IL10 • SORT1 • TNFA

Inhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy. (PubMed, Research (Wash D C)) - "Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field."

Journal • Review • Colorectal Cancer • Dyslipidemia • Gastrointestinal Cancer • Oncology • Solid Tumor

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study. (PubMed, Biomedicines) - "Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

Computational Design, Synthesis, and Biological Evaluation of Diimidazole Analogues Endowed with Dual PCSK9/HMG-CoAR-Inhibiting Activity. (PubMed, J Med Chem) - "In fact, carrying out biological assays to fully characterize the cholesterol-lowering activity of the new analogues and using both biochemical and cellular techniques, compound Dim16 displayed improved PCSK9 inhibitory activity (IC 0.9 nM). Interestingly, similar to other lupin-derived peptides and their synthetic analogues, some compounds in this series showed dual hypocholesterolemic activity since some of them complementarily inhibited the 3-hydroxy-3-methylglutaryl coenzyme A reductase."

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders

Identification of Potent Small-Molecule PCSK9 Inhibitors Based on Quantitative Structure-Activity Relationship, Pharmacophore Modeling, and Molecular Docking Procedure. (PubMed, Curr Probl Cardiol) - "ZINC000011726230 with energy binding: -11.4 kcal/mol and three H-bonds, ZINC000068248147 with binding affinity: -10.7 kcal/mol and one H-bond, ZINC000029134440 with a binding affinity: -10.6 kcal/mol and four H-bonds were ranked next, respectively. To conclude, the archived molecules identified as inhibitory PCSK9 candidates, and especially ZINC000051951669 may therefore significantly inhibit PCSK9 and should be considered in the newly designed trials."

Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Heart Failure

Clearance of plasma PCSK9 via the asialoglycoprotein receptor mediated by heterobifunctional ligands. (PubMed, Cell Chem Biol) - "Various formats, including bispecific antibodies, antibody-small molecule conjugates, and heterobifunctional small molecules, demonstrate binding in vitro and accelerated PCSK9 clearance in vivo. These molecules showcase a new approach to PCSK9 inhibition, targeted plasma protein degradation (TPPD), and demonstrate the feasibility of heterobifunctional small molecule ligands to accelerate the clearance and degradation of pathogenic proteins in circulation."

Journal • Dyslipidemia • Targeted Protein Degradation • ASGR • MUC4

Novel Target Study to Cure Cardiovascular Disease regarding Proprotein Converse Subtilisin/Kexin Type 9. (PubMed, Biomed Res Int) - "Molecular dynamics simulation analysis demonstrated that these two complex ZINC000004099069- and ZINC000014952116-PCSK9 had more favorable potential energy compared to the reference ligand, which could exist stably whether in vivo or in vitro. This study elucidated that ZINC000004099069 and ZINC000014952116 were finally screened as safe and potential drug candidates, which may have great significance in the development of PCSK9 inhibitor development."

Journal • Cardiovascular • Hepatology