PF 429242 / Pfizer - LARVOL DELTA

Pretreatment with serine protease inhibitors impairs Leishmania amazonensis survival on macrophages. (PubMed, Parasit Vectors) - "This work highlights the importance of serine proteases in L. amazonensis as a possible target for new therapeutic alternatives in Leishmania spp."

Journal • Infectious Disease

Acute heat stress regulates estradiol synthesis in ovine ovarian granulosa cells through the SREBPs/MVK-LHR pathway. (PubMed, Anim Reprod Sci) - "The cholesterol synthesis inhibitor, PF-429242, alleviated the decrease in estradiol synthesis caused by acute heat stress. Overall, acute heat stress caused a decrease in total cholesterol, which transactivated the expression of cholesterol synthesis genes, such as SREBP-1A, SREBP2, and MVK, increasing the MVK-LHR complex, downregulating LHR expression, and further decreasing estradiol."

Journal • CYP19A1

Collecting Duct Pro(Renin) Receptor Contributes to Unilateral Ureteral Obstruction-Induced Kidney Injury via Activation of the Intrarenal RAS. (PubMed, Hypertension) - "We examined the impact of CD-specific deletion of PRR, CD-specific deletion of renin, and S1P (site-1 protease) inhibitor PF429242 treatment on renal fibrosis and inflammation and the indices of the intrarenal RAS in a mouse model of unilateral ureteral obstruction...Similar results were obtained via pharmacological inhibition of S1P, the key protease for the generation of soluble PRR. Our results reveal that PRR-dependent/soluble PRR-dependent activation of CD renin represents a key determinant of the intrarenal RAS and, thus, obstruction-induced renal inflammation and fibrosis."

Journal • Cardiovascular • Fibrosis • Hypertension • Immunology • Inflammation • Nephrology • Renal Disease

DIFFERENTIATING ERYTHROBLASTS ADAPT TO TURBULENT FLOW BY ACCELERATING MATURATION AND ACTIVATING CHOLESTEROL BIOSYNTHESIS (EHA 2024) - "The inhibition of HMGCR and of Site-1 protease, were performed on day 0 ofdifferentiation using Lovastatin and PF-429242 respectively and their effects evaluated by flowcytometrystaining of CD234a/CD49d... The data show the ability of EBL to adapt to shear stress through modulation of their transcriptional programto upregulate cholesterol biosynthesis, which results essential to withstand turbulent flow. This work sheds lightinto specific mechanisms that will assist the successful upscaling of erythroid differentiation in turbulentbioreactors. In addition, as shear-stress on hematopoietic cells is also occurring within the bone marrow niche,these results introduce a potential novel signalling axis that need to be integrated into the known transductionpathways that control erythropoiesis."

Dyslipidemia • GYPA • ITGA4

Apelin-13: A Novel Approach to Suppressing Renin Production in RVHT. (PubMed, Am J Physiol Cell Physiol) - "Recombinant sPRR (sPRR-His) stimulated renin production, which was inhibited by PRR decoy peptide PRO20 and S1P inhibitor PF429242. These findings suggest that apelin-13 inhibits plasma renin expression through the cAMP/PKA/sPRR pathway, providing a potential therapeutic approach for RVHT. Understanding the regulation of renin production is crucial for developing effective treatments."

Journal • Cardiovascular • Hypertension • ATP6AP2

PF-429242 exhibits anticancer activity in hepatocellular carcinoma cells via FOXO1-dependent autophagic cell death and IGFBP1-dependent anti-survival signaling. (PubMed, Am J Cancer Res) - "The in vivo anticancer activity of PF-429242 against HCC cells was demonstrated in a tumor xenograft mouse model. Therefore, PF-429242 is a potential anticancer agent to treat HCC by triggering FOXO1-dependent autophagic cell death and IGFBP1-mediated anti-survival signaling in parallel."

Journal • Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Genito-urinary Cancer • Glioblastoma • Hepatocellular Cancer • Hepatology • Oncology • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • IGFBP1

Altered Lipid Metabolism in IMiD/CELMoD Resistant Multiple Myeloma Confers Novel and Targetable Vulnerabilities (IMW 2023) - "A genome-wide loss-of-function CRISPR screen was carried out in Iberdomide (Iber)-resistant MM1s; gene effect scores were calculated with the Chronos model and compared to parental MM1s using data from the DepMap portal...Using unpaired patient RNA-seq data, lipid gene transcript levels were compared between 736 newly diagnosed patients and 270 patients relapsing on lenalidomide. Quantitative proteomic analysis identified common changes in lipid synthesis pathways, including the SREBP pathway, across the resistant cell lines... The development of IMiD/CELMoD resistance is associated with alterations in lipid metabolism, suggesting a role in resistance biology that may confer novel and targetable vulnerabilities."

Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • Oncology • SCD

B-Cell Receptor Signaling Modulates Cholesterol Biosynthesis in Diffuse Large B-Cell Lymphoma (ASH 2022) - "We either genetically knock out the expression of IgH using CRISPR/Cas9 or pharmacologically inhibited Src kinase (downstream of the BCR signaling) with Dasatinib in non-GCB DLBCL cell lines. In summary, cholesterol biosynthesis is tightly regulated by BCR signaling through SREBP2, specifically in non-GCB DLBCL. SREBP2 is a potential promising adjuvant therapeutic target for DLBCL as PF-429242 enhances responses to doxorubicin in cell lines expanding the therapeutic window of doxorubicin by increasing its efficacy."

Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Metabolic Disorders • Non-Hodgkin’s Lymphoma • Oncology • ACAT1 • CDK1 • DHCR7 • HMGCS1 • IGH • SYK

Multiomics Analysis of IMiD/CELMoD Resistant Multiple Myeloma Models Uncovers Novel and Targetable Vulnerabilities in the SREBP Lipid Synthesis Pathway (ASH 2022) - "Methods IMiD/CELMoD resistant human MM cell lines were generated by treating MM1s and H929 cells with lenalidomide (Len), pomalidomide (Pom) or iberdomide (Iber) at ~10x GI50 concentration for ~12 weeks until resistance was achieved...The activity of PF-429242, an inhibitor of MBTPS1, was explored in the resistant lines...High SCD or MBTPS1 mRNA expression was associated with significantly worse PFS (logrank p<0.01), providing a further rationale for targeting the pathway. Conclusions Models representing multiple different IMiD/CELMoD resistance mechanisms have unified alterations in the SREBP pathway, highlighting a role in resistance biology and potential novel and targetable vulnerabilities."

Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • SCD

Insulin can up-regulate LC-PUFA biosynthesis with the involvement of Srebp-1c and stimulatory protein 1 (Sp1) in marine teleost Siganus canaliculatus. (PubMed, Gene) - "Besides, inhibitors of transcription factors Srebp-1c (Fatostatin, PF-429242) and Sp1 (Mithramycin) could inhibit the gene expression of Srebp-1c, Δ6/Δ5 fads and elovl5, and abolish the up-regulation of INS on these genes' expression and LC-PUFA biosynthesis. These results indicated that INS could up-regulate LC-PUFA biosynthesis with the involvement of Srebp-1c and Sp1 in rabbitfish S. canaliculatus, which is the first report in teleost."

Journal

Evaluation of Aminopyrrolidine Amide to improve chloride transport in CFTR-defective cells. (PubMed, Bioorg Med Chem Lett) - "We also observed that PF-429242 alleviates the defects of the p.Phe508del-CFTR channel in human Cystic Fibrosis cells. Our results suggest that aminopyrrolidine amide is a potential therapeutic target for Cystic Fibrosis that could also have beneficial effects in other diseases involving CFTR, such as the Chronic Obstructive Pulmonary Disease."

Journal • Chronic Obstructive Pulmonary Disease • Cystic Fibrosis • Fibrosis • Genetic Disorders • Immunology • Pulmonary Disease • Respiratory Diseases • ATF6 • CFTR

Subtilisin of Leishmania amazonensis as Potential Druggable Target: Subcellular Localization, In Vitro Leishmanicidal Activity and Molecular Docking of PF-429242, a Subtilisin Inhibitor. (PubMed, Curr Issues Mol Biol) - "We detected by flow cytometry that there is a greater expression of subtilisin in the amastigote form; however, PF-429242 had a low effect against this intracellular form with an IC50 of >100 µM for intracellular amastigotes, as well as against axenic amastigotes (94.12 ± 2.8 µM for the LV78 strain). In conclusion, even though PF-429242 does not affect the intracellular forms, this drug will serve as a tool to explore pharmacological and potentially leishmanicidal targets."

Journal • Preclinical • Dengue Fever • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Simvastatin Resistance of Leishmania amazonensis Induces Sterol Remodeling and Cross-Resistance to Sterol Pathway and Serine Protease Inhibitors. (PubMed, Microorganisms) - "LaSimR was cross-resistance to ketoconazole (a C14DM inhibitor) and remained sensitive to terbinafine (an inhibitor of squalene monooxygenase). Sensitivity of the LaSimR mutant to other antileishmanial drugs unrelated to the sterol biosynthesis pathway, such as trivalent antimony and pentamidine, was similar to that of the wild-type strain; however, LaSimR was cross-resistant to miltefosine, general serine protease inhibitor N-p-tosyl-l-phenylalanine chloromethyl ketone (TPCK), subtilisin-specific inhibitor 4-[(diethylamino)methyl]-N-[2-(2-methoxyphenyl)ethyl]-N-(3R)-3-pyrrolidinyl-benzamide dihydrochloride (PF-429242), and tunicamycin. The findings on the regulation of the sterol pathway can support the development of drugs and protease inhibitors targeting this route in parasites."

Journal

ROLE OF S1P-DERIVED SOLUBLE (PRO)RENIN RECEPTOR IN ALBUMIN OVERLOAD INDUCED NEPROPATHY IN 129/SV MICE (ISN-WCN 2022) - " 129/Sv mice were treated for 4 weeks with AO alone or in conjunction with S1P inhibitor PF-429242 (PF) (10 mg/kg/d via by implanting osmotic pumps subcutaneously), as well as sham control group. Compared with the sham control, the AO rats exhibited significant increases in sPRR excretion, proteinuria, urinary N-acetyl-β-D-glucosaminidase (NAG) activity, renin activity, Ang Ⅱ, and IL-6, IL-8, vascular cell adhesion protein 1 (vascular cell adhesion protein 1, VCAM-1) and intercell adhesion molecule 1 (intercellular adhesion molecule 1, ICAM-1) in mice kidney. In summary, our findings demonstrated that S1P antagonism with PF ameliorates AO-induced nephropathy mainly through inhibition of intrarenal RAS and NOX-4/ NF-ҡB signaling pathway."

Preclinical • Fibrosis • Immunology • Renal Disease • CXCL8 • ICAM1 • IL6 • VCAM1

Advanced Oxidation Protein Product Promotes Oxidative Accentuation in Renal Epithelial Cells via the Soluble (Pro)renin Receptor-Mediated Intrarenal Renin-Angiotensin System and Nox4-HO Signaling. (PubMed, Oxid Med Cell Longev) - "Treatment of HK-2 cells with the site-1 protease (S1P) inhibitor PF429242 (40 μM) or S1P siRNA significantly inhibited AOPP-induced sPRR generation...Increased renal proximal tubule Nox4-derived HO contributed to the aggravation of oxidative stress. Targeting S1P-derived sPRR is a promising intervention strategy for chronic kidney disease."

Journal • Chronic Kidney Disease • Nephrology • Renal Disease • ATP6AP2

The (pro)renin receptor and soluble (pro)renin receptor in choriocarcinoma. (PubMed, Reproduction) - "BeWo choriocarcinoma cells were treated with ATP6AP2 siRNA, FURIN siRNA, DEC-RVKR-CMK (to inhibit FURIN activity) or PF 429242 (to inhibit MBTPS1 activity)...We postulate that sATP6AP2 could be used as a biomarker measuring the invasive potential of choriocarcinomas. Additionally, we confirmed that FURIN, not MBTPS1, cleaves sATP6AP2 in BeWo cells, but other proteases (inhibited by DEC-RVKR-CMK) may also be involved."

Journal • Oncology • ATP6AP2 • CDH1

SREBP1 site 1 protease inhibitor PF-429242 suppresses renal cell carcinoma cell growth. (PubMed, Cell Death Dis) - "SREBP1, S1P, and its target gene low density lipoprotein receptor (LDLR) were significantly elevated in human RCC tissues. These results suggest that targeting S1P by PF-429242 inhibited RCC cell growth in vitro and in vivo."

Journal • Dyslipidemia • Genetic Disorders • Genito-urinary Cancer • Immunology • Oncology • Primary Immunodeficiency • Renal Cell Carcinoma • Solid Tumor

The novel therapeutic target and inhibitory effects of PF-429242 against Zika virus infection. (PubMed, Antiviral Res) - "Fenofibrate, an inhibitor of lipid droplet formation, reduces the ZIKV titer. In addition, this study reveals that the mechanism of the PF-429242-mediated suppression among flavivirus infections is not entirely identical. Our results warrant further evaluation of PF-429242 as a prospective antiviral drug, given the multiple advantageous properties of this compound, such as its limited toxicity, neuroprotective properties, and broad spectrum of capabilities."

Journal • Infectious Disease • Metabolic Disorders

[VIRTUAL] Advanced oxidation protein products activate oxidative stress in vitro via soluble (pro)renin receptor mediated intrarenal renin angiotensin system and Nox4/H2O2 pathway (ISN-WCN 2021) - "What’s more, PF-429242 significantly decreased AOPPs stimulated Nox4 and H2O2 expression and administration of a recombinant sPRR, termed sPRR-His, reversed the effects of S1P inhibition. Conclusions Taken together, these findings suggest that AOPPs induce oxidative stress via S1P-derived soluble (pro)renin receptor activation intrarenal renin angiotensin system and Nox4/H2O2 pathway in vitro."

Preclinical • ADAM9 • ICAM1 • TNFA

PF-429242, a Subtilisin Inhibitor, Is Effective in vitro Against Leishmania infantum. (PubMed, Front Microbiol) - "The compound did not stimulate ROS or IL-10 production. Together, these data highlight the antileishmanial potential of PF-429242, inducing several cellular alterations in the parasite, such as mitochondrial damage, neutral lipids accumulation, oxidative stress and autophagy which culminate in the death of L. infantum, as well as modulating host cellular responses that favor the development of an immune response against the parasite."

Journal • Preclinical • Infectious Disease • IL10

Novel cholesterol-dependent regulation of cardiac K subunit expression revealed using histone deacetylase inhibitors. (PubMed, Physiol Rep) - "Lastly, HL-1 cardiomyocytes treated with the SREBP inhibitor PF429242 significantly suppresses the effect of TSA on SUR2 gene expression. These results demonstrate that SREBP is an important regulator of K channel expression and suggest a novel method by which hypercholesterolemia may exert negative effects on the cardiovascular system, namely, by suppressing expression of the K channel."

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders • MED23

Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II-Induced Hypertension in Mice. (PubMed, Hypertension) - "F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry...Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II-induced hypertension through enhancement of intrarenal renin level and activation of ENaC."

Journal • Hypertension

Cleavage of the soluble (pro)renin receptor (sATP6AP2) in the placenta. (PubMed, Placenta) - "Soluble ATP6AP2 is secreted by placental trophoblasts and levels decrease with syncytialisation. DEC-RVKR-CMK, a broad inhibitor of pro-protein convertases reduced extracellular sATP6AP2 levels, but FURIN siRNA and MBTPS1 inhibition had no effect. Hence, a convertase other than FURIN or MBTPS1 is most likely responsible for placental sATP6AP2 secretion."

Journal • Diabetes • Gestational Diabetes • Gynecology • Metabolic Disorders

Soluble (pro)renin receptor promotes fibrotic response in renal proximal tubule epithelial cells in vitro via Akt/β-catenin/Snail signaling pathway. (PubMed, Am J Physiol Renal Physiol) - "To explore the role of sPRR in fibrotic response of HK-2 cells, we blocked the production of sPRR with a S1P inhibitor PF429242 and found that PF429242 remarkably suppressed TGF-β induced sPRR generation and FN expression in HK-2 cells...Mechanistically, sPRR activated the AKT and β-catenin pathway in HK-2 cells, and blockade of AKT or β-catenin pathway significantly abrogated sPRR-induced FN and Snail expression. Taking together, sPRR promoted the fibrotic response of HK-2 cells by activating Akt/β-catenin/Snail signaling, and it may serve as a potential therapeutic target in renal fibrosis."

Journal • Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease

Soluble (Pro)Renin Receptor Regulation of ENaC Involved in Aldosterone Signaling in Cultured Collecting Duct Cells. (PubMed, Am J Physiol Renal Physiol) - "In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM within minutes induced a significant and transient increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique. Medium sPRR was elevated by Aldo and inhibited by PF. Taken together, these results demonstrate that sPRR induces two phases of ENaC activation via distinct mechanisms and functions as a mediator of the natriferic action of Aldo."

Journal • Preclinical