Their activity was associated with HDAC6 inhibition below 2 nM, blockade of AKT2 phosphorylation at 2 μM, and synergistic reversal of venetoclax resistance in two cancer models. These findings validate our modeling approach for predicting hybrid inhibitors and highlight 6b and 6k as promising leads for hematological cancer therapy.

This aided the identification of 6b and 6k as potent anticancer inhibitors with IC 50 of 0.2-0.8 µM in three cancer cell lines, linked to HDAC6 inhibition below 2 nM, and blockade of AKT2 phosphorylation at 2 μM, validating the ability of our models to predict novel drug candidates. Novel kinase/HDAC inhibitors for cancer treatment were found using machine learning61 QSAR models for hematological cancers and its targets were built and validatedK562, MV4-11, MM1S, NB-4, U937, and HDAC6 models had hit rates above 62.5% in tests 6b and 6k presented potent IC 50 of 0.2-0.8 µM in three cancer cell lines 6b and 6k inhibited HDAC6 below 2 nM, and blockade of AKT2 phosphorylation at 2 μM.

GSK690693 or si-AMPK was applied to block AMPK pathway...Finally, we demonstrated that WNK1 regulated the malignant behaviors of HCC cells by modulating autophagy and AMPK pathway. The above results indicated that WNK1 may be a worthwhile target to be considered for therapy of HCC.

P2, N=96, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting

AKT2 overexpression or miR-506-3p inhibition restored the suppression of growth and invasiveness of CRC cancer cells caused by circPTK2 silencing. The circPTK2/miR-506-3p/AKT2 axis plays a novel and essential role in promoting CRC progression, providing potential targets for CRC therapeutic modality.

The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part Phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

Analysis of data from the Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 messenger RNA and protein levels were significantly higher in patients with HCC and associated with clinical pathological parameters. In contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in patients with HCC.

Inhibition of the AKT signaling cascade by GSK690693 may serve as an alternative to improve the irinotecan response in EVI1-expressing colon cancer cells.

Using a xenograft orthotopic model of breast tumorigenesis (4T1-Pcbp1), we show here that PCBP1 knockdown-induced tumorigenesis is inhibited by activation of the WNT signaling via treating with the glycogen synthase kinase 3 beta inhibitor TWS119, but not the Akt2/Akt3 inhibitor GSK690693...Using cytotoxic T cells isolated from healthy donors, we show that TWS119-induced WNT signaling-mediated inhibition of cytotoxic T cell expansion is reliant on expression of PCBP1. In conclusion, decreased PCBP1 expression favors breast tumorigenesis by potentiating skewing of tumor infiltrating T cells towards Tregs, thereby effectively suppressing anti-tumor immunity.

Taken together, the AKT2-catalyzed phosphorylation of Fascin Threonine 403 suppressed esophageal cancer cell behavior, actin-bundling activity, and filopodia formation. DATA AVAILABILITY STATEMENT: The datasets for this study can be found in the TCGA database (https://tcga-data.nci.nih.gov/tcga/) and GTEx databases (http://commonfund.nih.gov/GTEx/).

These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume)...Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.

Additionally, the results of the Lipinski rule of five indicated that some of the selected compounds, such as dieckol, 6,6'-bieckol and siphonaxanthin, violated some Lipinski rules, but they demonstrated excellent binding in terms of scoring. Thus, this study demonstrates that the identified lead compounds may act against Akt1 and Akt2 in oral cancer.