Discovery of 2,3′-diindolylmethanes as a novel class of PCSK9 modulators

Winston‐McPherson, Gabrielle N.; Xie, Haibo; Yang, Kuo‐Ho; Li, Xiaoxun; Shu, Dongxu; Tang, Weiping

doi:10.1016/j.bmcl.2019.06.014

Cited by 8 publications

(2 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our approach also documents significant increases in the plasma levels of indole and indoleacrylic acid (IA) after a 12 week administration of PCSK9i. Indole and indole derivatives play a key role in the pharmaceutical development of new potent metabolically stable PCSK9 modulators [57][58][59]. Indeed, an indole alkaloid from Nauclea latifolia inhibits PCSK9 and promotes LDL uptake in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

et al. 2021

View full text Add to dashboard Cite

Introduction: Familial hypercholesterolemia (FH) is characterized by extremely high levels of circulating low-density lipoprotein cholesterol (LDL-C) and is caused by mutations of genes involved in LDL-C metabolism, including LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/Kexin type 9 (PCSK9). Accordingly, PCSK9 inhibitors (PCSK9i) are effective in LDL-C reduction. However, no data are available on the pleiotropic effect of PCSK9i. To this end, we performed an untargeted metabolomics approach to gather a global view on changes in metabolic pathways in patients receiving treatment with PCSK9i. Methods: Twenty-five FH patients starting treatment with PCSK-9i were evaluated by an untargeted metabolomics approach at baseline (before PCSK9i treatment) and after 12 weeks of treatment. Results: All the 25 FH subjects enrolled were on maximal tolerated lipid-lowering therapy prior to study entry. After a 12 week treatment with PCSK9i, we observed an expected significant reduction in LDL-cholesterol levels (from 201.0 ± 69.5 mg/dL to 103.0 ± 58.0 mg/dL, p < 0.001). The LDL-C target was achieved in 36% of patients. After peak validation and correction, after 12 weeks of PCSK9i treatment as compared to baseline, we observed increments in creatine (p-value = 0.041), indole (p-value = 0.045), and indoleacrylic acid (p-value= 0.045) concentrations. Conversely, significant decreases in choline (p-value = 0.045) and phosphatidylcholine (p-value < 0.01) together with a reduction in platelet activating factor (p-value = 0.041) were observed. Conclusions: Taking advantage of untargeted metabolomics, we first provided evidence of concomitant reductions in inflammation and platelet activation metabolites in FH patients receiving a 12 week treatment with PCSK9i.

show abstract

Section: Discussionmentioning

confidence: 99%

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

et al. 2021

View full text Add to dashboard Cite

show abstract

“…For instance, Winston-McPherson et al discovered a difluoro-2,3’-diindolylmethane (DFDIM) skeleton small molecule inhibitor that can decrease the expression of PCSK9 with half-maximal inhibitory concentration (IC50) ≈ 200 nM in cell line model. 408 Wang et al successfully identified an effective small-molecule of PCSK9 inhibitor 7030B-C5 (IC50 = 1.61 μM), which significantly reduced plasma cholesterol and TG levels and retarded atherosclerosis progression in vivo. 61 , 409 Nagiec et al identified a series of novel PCSK9 antagonists such as BRD8518 (half-maximal effective concentration [EC50] = 0.23 μM) by screening the diversity-oriented synthesis (DOS)-derived small-molecule library for compounds that upregulated expression of lipid metabolic gene TRIB1 .…”

Section: Pcsk9 As a Potential Target For Multiple Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

View full text Add to dashboard Cite

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

show abstract

Identification of Potent Small-Molecule PCSK9 Inhibitors Based on Quantitative Structure-Activity Relationship, Pharmacophore Modeling, and Molecular Docking Procedure

Mahmoudi

Butler

Banach

et al. 2023

Current Problems in Cardiology

View full text Add to dashboard Cite

Discovery of 2,3′-diindolylmethanes as a novel class of PCSK9 modulators

Cited by 8 publications

References 40 publications

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

Treatment with PCSK9 Inhibitors in Patients with Familial Hypercholesterolemia Lowers Plasma Levels of Platelet-Activating Factor and Its Precursors: A Combined Metabolomic and Lipidomic Approach

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Identification of Potent Small-Molecule PCSK9 Inhibitors Based on Quantitative Structure-Activity Relationship, Pharmacophore Modeling, and Molecular Docking Procedure

Contact Info

Product

Resources

About