PF-06446846 / Pfizer - LARVOL DELTA

Triterpenoids and Lignans From Schisandra henryi subsp. yunnanensis A. C. Smith. (PubMed, Chem Biodivers) - "In bioactivity evaluation, the isolated triterpenoids (1-10) exhibited moderate neurite outgrowth in differentiated PC12 cells at 10 µM (differentiation rates 10.09%-12.96%; positive control 50 ng/mL NGF, 19.71%). Furthermore, henridilactone P (1) exhibited a binding affinity with an equilibrium dissociation constant (KD) of 3.286 × 10- 4 M (reference compound PF-06446846, KD = 8.008 × 10- 5 M)."

Journal

Mechanism of PCSK9-Mediated Macrophage Activation via the CAP1/NF-κB Pathway in CAWS-Induced Kawasaki Disease Vasculitis. (PubMed, IUBMB Life) - "PCSK9 was pharmacologically inhibited in vivo with SBC-115076 and in vitro with PF-06446846...PCSK9 promotes KD-like vasculitis by activating the CAP1-mediated NF-κB pathway in macrophages, thereby driving pro-inflammatory responses. Pharmacological inhibition of PCSK9 attenuates vascular immunopathology, highlighting PCSK9 as a potential therapeutic target for KD."

Journal • Infectious Disease • Inflammation • Vasculitis • CD86 • IL1B • IL6 • PCSK9 • TNFA

IDENTIFYING PCSK9 AS A POTENTIAL THERAPEUTIC CO-TARGET IN METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA, THROUGH INTEGRATED TRANSCRIPTOMIC AND PROTEOMIC ANALYSIS (UEGW 2025) - "Proprotein convertase subtilisin/kexin type 9 (PCSK9) expression was reduced using shRNA, or pharmacological inhibition via small molecule PF846, and monoclonal antibody inhibitor evolocumab ± chemotherapies gemcitabine/nab-paclitaxel (GNP). Overall, this work identifies PCSK9 as a novel 'druggable' target and presents a potential opportunity to repurpose FDA/TGA-approved inhibitor evolocumab in PDAC. Ongoing work involves utilising patient-derived xenograft models to assess PCSK9 inhibition ± chemotherapy in a clinically-relevant setting."

Metastases • Omic analysis • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Targeted Protein Degradation • CASP3 • PCSK9

Dual-targeted albumin nanoparticles for the Co-delivery of low-dose paclitaxel and PCSK9 inhibitor in melanoma treatment. (PubMed, Mater Today Bio) - "We developed hyaluronic acid/R8-RGD dual-modified albumin nanoparticles (HR/LDPP-NPs) designed to co-deliver low-dose paclitaxel (PTX) and the PCSK9 inhibitor PF-06446846. This synergistic approach, combining in situ vaccination with enhanced antigen presentation, significantly amplifies antitumor immunity. Both in vitro and in vivo experiments demonstrate that these spatiotemporally coordinated dual-targeting nanoparticles achieve substantial therapeutic efficacy with significantly reduced toxicity, presenting a novel chemo-immunotherapeutic strategy for melanoma treatment."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • CALR • HMGB1

Small molecule inhibitors of PCSK9. SAR investigations of head and amine groups. (PubMed, Bioorg Med Chem Lett) - "Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1)...Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate."

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PCSK9 expression in liver sinusoidal endothelial cells during liver metastasis (AACR 2023) - "Furthermore, we inhibited PCSK9 with siRNA and chemical inhibitor (PF-06446846)...We can conclude that PCSK9 plays a key role in LSEC during Liver Colorectal Metastasis affecting significantly on proliferation and showing a particular nuclear location. Although the metabolic pathway remains undetermined, the proteomic and RNAseq studies have provided us with some molecules that seem to interact with PCSK9 and that could explain the particular function of PCSK9 in LSECs during the metastatic process"

Colorectal Cancer • Gastrointestinal Cancer • Oncology • CD31 • CDK6 • ERN1 • PCSK9 • PECAM1

An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy. (PubMed, Small) - "After immune response trigged by O-TMV antigen, the 4-1BB antibody-promoted T cell mitochondrial biogenesis and the axitinib-lowered hypoxia synergistically reverse T cell exhaustion while the PF-06446846-amplified MHC I expression facilitates T cell recognition of tumor cells, demonstrating a powerful immunotherapeutic efficacy. This strategy on reprograming T cell exhaustion and improving T cell potency offers new concept for T cells-based cancer immunotherapy."

IO biomarker • Journal • Metabolic Disorders • Oncology

Compounds for selective translational inhibition. (PubMed, Curr Opin Chem Biol) - "Indeed, this technique uncovers the selectivity of translation repression by small molecules such as chloramphenicol, macrolides, PF846, and rocaglates. The molecular understanding of how the compounds inspire context selectivity, despite their targeting to general translation machinery, facilitates rational drug design and discovery for therapeutic purposes."

Journal • Review

[VIRTUAL] METASTASIC COLON CANCER CELL SECRETOME TRIGGERS PCSK9 OVEREXPRESSION IN LIVER SINUSOIDAL ENDOTHELIAL CELLS AND IT IS INVOLVED IN CELL MOTILITY (AASLD 2021) - "PCSK9 inhibition by PF-06446846 reduce liver sinusoidal endothelial cells motility... We described PCSK9 expression in liver sinusoidal endothelial cells for the first time and the expression pattern differs from hepatocytes. In hepatocytes, PCSK9 is a soluble protein able to join to LDL cholesterol cell membrane receptor . We localized PCSK9 in liver sinusoidal endothelial cells in cytoplasm and nucleus suggesting functions focused on protein carrier or transcription factor ."

Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PCSK9 • PDGFB • PDGFRA • SOX2