AT7867 / Otsuka - LARVOL DELTA

AT7867 promotes pancreatic progenitor differentiation of human iPSCs. (PubMed, Stem Cell Reports) - "Transplantation of AT7867-treated PPs resulted in faster hyperglycemia reversal in diabetic mice compared with controls (time and group: p < 0.0001). Overall, our data show that AT7867 enhances PP cell differentiation leading to accelerated diabetes reversal."

Journal • Diabetes • Metabolic Disorders • Transplantation • PDX1 • PODXL

Molecular insights into the behavior of the allosteric and ATP-competitive inhibitors in interaction with AKT1 protein: A molecular dynamics study. (PubMed, Int J Biol Macromol) - "We studied the effects of four inhibitors, including MK-2206, Miransertib, Herbacetin, and Shogaol, on the inactive conformation of AKT1 protein and the effects of four inhibitors, Capivasertib, AT7867, Quercetin, and Oridonin molecules on the active conformation of AKT1 protein. As compared to other complexes in either of its two conformations, MK-2206 has a stronger binding free energy affinity in the inactive conformation, -203.446 kJ/mol. MM-PBSA calculations showed that the van der Waals interactions contribute more than the electrostatic interactions to the binding energy of inhibitors to AKT1 protein."

Journal • AKT1

AT7867 Inhibits the Growth of Colorectal Cancer Stem-Like Cells and Stemness by Regulating the Stem Cell Maintenance Factor Ascl2 and Akt Signaling. (PubMed, Stem Cells Int) - "Furthermore, compared with other Akt inhibitors, AT7867 could promote the differentiation of colorectal cancer stem cells. Thus, AT7867 might be a potential antitumor drug candidate to treat CRC by targeting CSCs."

IO biomarker • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Identification of kinase inhibitors that rule out the CYP27B1-mediated activation of vitamin D: an integrated machine learning and structure-based drug designing approach. (PubMed, Mol Divers) - "Tyrosine kinase inhibitor such as imatinib is reported to interfere with the activation of vitamin D by inhibiting CYP27B1 enzyme. This model was further employed for the virtual screening of kinase inhibitors from the binding database (DB), which tend to interfere with the CYP27B1-mediated activation of vitamin D. This screening yielded around 4646 kinase inhibitors that were further subjected to structure-based analyses using the homology model of CYP27B1, as the 3D structure of CYP27B1 complexed with heme was not available. Overall, five kinase inhibitors including two well-known drugs, i.e., AT7867 (Compound-2) and amitriptyline N-oxide (Compound-3), were found to interact with CYP27B1 in such a way that may preclude the conversion of vitamin D to its active form and hence testify the impairment of vitamin D activation pathway."

Journal • Oncology

Dual Inhibition of AKT and MEK Pathways Potentiates the Anti-Cancer Effect of Gefitinib in Triple-Negative Breast Cancer Cells. (PubMed, Cancers (Basel)) - "As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells."

Journal • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Solid Tumor • Thymoma • Thymus Cancer • Triple Negative Breast Cancer • EGFR

Combined Omics Approaches Reveal the Roles of Non-canonical WNT7B Signaling and YY1 in the Proliferation of Human Pancreatic Progenitor Cells. (PubMed, Cell Chem Biol) - "A comparison of the phosphoproteome in response to AT7867 or a newly synthesized AT7867 derivative uncovered the function of YY1 as a transcriptional regulator of WNT7B. Overall, our data highlight unknown roles of non-canonical WNT7B/PKC signaling and YY1 in human PPC proliferation and will contribute to the stable supply of a cell source for pancreatic disease modeling and therapeutic applications."

Journal • Diabetes • Gastrointestinal Disorder • Hepatology • Metabolic Disorders • Pancreatitis

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms. (PubMed, PLoS One) - "We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs...Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter...Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression."

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