PF-3814735 / Pfizer - LARVOL DELTA

A reanalysis and integration of transcriptomics and proteomics datasets unveil novel drug targets for Mekong schistosomiasis. (PubMed, Sci Rep) - "Despite efforts to combat it, the rise of praziquantel (PZQ) resistance underscores the need for new treatment options...FAK inhibitor 14 and PF-03814735 exhibited strong binding to Schistosoma FAK with minimal binding for human FAK...However, further research, including in vivo studies, is necessary to validate efficacy and safety before clinical use. This study offers a hopeful strategy to combat schistosomiasis and reduce its global impact."

Journal • Infectious Disease

Inhibitors of One or More Cellular Aurora Kinases Impair the Replication of Herpes Simplex Virus 1 and Other DNA and RNA Viruses with Diverse Genomes and Life Cycles. (PubMed, Microbiol Spectr) - "The compounds TAK 901, JNJ 7706621, and PF 03814735 decreased HSV-1 titers by 4,500-, 13,200-, and 8,400-fold, respectively, when present in a low micromolar range. Together, our results illustrate a novel role for aurora kinases in the HSV-1 lytic cycle and demonstrate that aurora kinase inhibitors can restrict HSV-1 replication. Furthermore, these aurora kinase inhibitors also reduced the replication of murine coronavirus and vaccinia virus, suggesting that multiple viral families utilize the aurora kinases for their own replication."

Journal • Hepatology • Herpes Simplex • Infectious Disease • Inflammation • Novel Coronavirus Disease

Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity. (PubMed, ACS Chem Biol) - "Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Neuroendocrine Tumor • Obesity • Solid Tumor • Type 2 Diabetes Mellitus

Aurora kinase: A target modulating invasiveness of lung adenocarcinoma (AACR 2018) - "We used two potent aurora kinase inhibitors AMG 900 and PF-03814735 to determine the effect of aurora kinase inhibition on invasiveness of LUAD cells. Here, we have identified a robust gene signature that distinguishes invasive to indolent non-invasive early-stage LUADs, which may lead to development of assays on clinical specimens such as biopsy to identify patients at high risk of developing invasive LUAD at an early stage. This gene signature also suggests Aur-A and B promote invasiveness in early stage LUAD. Our in vitro functional data suggest that targeting Aur-A and B could be a promising approach for management of early stage LUAD patients who are more likely to develop an invasive tumor."

Non Small Cell Lung Cancer

[VIRTUAL] Aurora Kinase: Master Regulator of Invasiveness in Early Stage Lung Adenocarcinoma (ATS-I 2020) - "Pan- Aurora kinase (Aur-) inhibitors (AMG900, PF-03814735) and CRISPR/Cas9 knockout of AURKA and AURKB were used to evaluate the effect of Aur- inhibition on invasiveness of LUAD by migration, invasion and wound healing assays... Here, we have identified a robust gene signature that distinguishes invasive and indolent early-stage LUAD tumors. Our data reveals Aur- A and B co-operatively mediate invasiveness in LUAD through EMT and AKT/mTOR/MMP pathway. Our findings suggest use of Aur- inhibitors as adjuvant therapy, could benefit subset of LUAD patients representing an invasive phenotype at early stage."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • AURKA

An integrated genomic approach to identify predictive biomarkers of response to the Aurora kinase inhibitor PF-03814735 (Mol Cancer Ther) - SCLC & to a lesser extent colon cancer lines were very sensitive to PF-03814735; In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc genes driven models to PF-03814735 & possible schedule dependence of MYC/c-Myc driven tumors

Preclinical-animal • Preclinical-other • Oncology

Toward In Vitro Epigenetic Drug Design for Thyroid Cancer: The Promise of PF-03814735, an Aurora Kinase Inhibitor. (PubMed, OMICS) - "PF-03814735, a small-molecule inhibitor of Aurora kinase A (IC = 0.8 nM) and B (IC = 5 nM), was the most potent on KTC2 cells, whereas CUDC-101, a multitarget inhibitor, was effective on both WRO and KTC2 cells. In conclusion, these new findings offer specific guidance on dose and time course selection to design novel therapeutic interventions against TC using PF-03814735, and specifically target cells carrying the TERTp mutation. In a larger context of drug discovery science, these findings inform new strategies to forecast optimal treatment regimens for TC, particularly with Aurora kinase inhibitors and in ways guided by epigenetic drug design."

Journal

Aurora Kinase: Master Regulator of Invasiveness in Early Stage Lung Adenocarcinoma (ATS 2020) - "Pan- Aurora kinase (Aur-) inhibitors (AMG900, PF-03814735) and CRISPR/Cas9 knockout of AURKA and AURKB were used to evaluate the effect of Aur- inhibition on invasiveness of LUAD by migration, invasion and wound healing assays... Here, we have identified a robust gene signature that distinguishes invasive and indolent early-stage LUAD tumors. Our data reveals Aur- A and B co-operatively mediate invasiveness in LUAD through EMT and AKT/mTOR/MMP pathway. Our findings suggest use of Aur- inhibitors as adjuvant therapy, could benefit subset of LUAD patients representing an invasive phenotype at early stage."

AURKA • GS

Characterization of in vitro metabolism of focal adhesion kinase inhibitors by LC/MS/MS. (PubMed, J Pharm Biomed Anal) - "To better understand biotransformation of FAK inhibitors, this work has investigated in vitro phase I metabolism of inhibitors (namely PF-573228, PF-562271 and PF-03814735) by rat liver microsomes model. For PF-562271, they were hydroxylation and dehydrogenation. Hydroxylation was observed as the primary metabolism for PF-0381473."

Journal • Preclinical