PF-06840003 / Pfizer, iTeos - LARVOL DELTA

Action mechanism and molecular design of indolepyrrodione inhibitors targeting IDO1. (PubMed, Front Mol Biosci) - "These findings suggest a potential inhibitory mechanism for PF-06840003 and offer valuable structural insights for the rational design of potent IDO1 inhibitors. It should be noted that the inhibitory activity of the designed lead compounds is based solely on computational predictions; experimental validation through in vitro and in vivo studies is still required to confirm their actual inhibitory effects and pharmacokinetic properties."

Journal • Oncology • IDO1

Mitochondria-targeted iridium(III)-PF-06840003 conjugates: Apoptosis induction, IDO inhibition and ICD response. (PubMed, J Inorg Biochem) - "This is manifested by a decrease in mitochondrial membrane potential (MMP) and an increase in reactive oxygen species (ROS) levels. During apoptosis and immunogenic cell death (ICD) induction, there is also G2/M phase cycle arrest."

Journal • Cervical Cancer • Oncology • Solid Tumor

Inhibition of indoleamine 2,3-dioxygenase 1 alleviates atopic dermatitis-like symptoms (EADV 2025) - "This study investigated the therapeutic effects of PF-06840003 (PF), a selective inhibitor for IDO1, in AD models...In vivo, an MC903-induced AD-like mice were administered with PF (5 ~ 15 mg/kg) or vehicle... PF exhibited potent anti-inflammatory and skin barrier-protective effects in both in vitro and in vivo models of AD, suggesting that IDO1 inhibition and regulation of tryptophan metabolism as a promising therapeutic strategy for skin inflammation such as AD."

IO biomarker • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • CCL2 • CCL3 • CLDN1 • CXCL8 • IDO1 • IL13 • IL1A • IL4 • IL6 • TJP1

IDO-1 inhibition improves outcome after fluid percussion injury in adult male rats. (PubMed, J Neurosci Res) - "In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice-daily oral administration of the IDO1 inhibitor PF-06840003 (100 mg/kg) or vehicle control...IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery."

Journal • Preclinical • CNS Disorders • Psychiatry • Vascular Neurology

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease. (PubMed, Curr Alzheimer Res) - "This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders

Investigating the effects of IDO1 inhibition on neurological recovery following experimental TBI (CAN-ACN 2022) - " Young adult male Sprague-Dawley rats underwent fluid percussion injury (FPI) or sham injury, followed by oral dosing of an IDO1 inhibitor (PF-06840003, 100 mg/kg) or vehicle ((2-Hydroxypropyl)- β-cyclodextrin (HBCD)) twice daily... Inhibition of IDO1 activity improves neurological function after experimental TBI. Further work is needed to determine the effect of IDO1 inhibition on specific KP metabolites and various secondary injury mechanisms after TBI."

CNS Disorders • Vascular Neurology

Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism. (PubMed, Cardiovasc Toxicol) - "Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling."

IO biomarker • Journal • Cardiovascular • Oncology • IDO1 • RPS6