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.

E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.

Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

Taiho Oncology, Inc. reviewed the abstract for scientific accuracy but had no significant input into the content.

Moreover, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) inhibitor U0126, p38 inhibitor SB205380, JNK inhibitor SP600125 and Akt inhibitor GSK 690693 decreased IL-1β-induced MMP-3 mRNA and protein expression. In conclusion, we have found that IL-1β induces the expression of MMP-3 through ERK1/2, JNK, p38 MAPK and Akt signaling pathways to enhance the migration of hUCMSCs. These results provide further understanding of the mechanisms in IL-1β-induced hUCMSCs migration to injury sites.

Moreover, UNC1999 and a selective Akt inhibitor TAS-117 synergistically inhibit the growth of MM cells through epigenetic mechanisms...Interestingly, a microtubule polymerization inhibitor PTC596 cooperatively downregulates BMI1 protein with proteasome inhibitors, exhibiting in-vitro and in-vivo cytotoxicity in MM cells. Finally, our mouse model with concurrent loss of the histone demethylase Utx and the activating mutation of Braf V600E in post germinal center B cells demonstrates mature B-cell malignancies including plasma cell neoplasms. Our ongoing analyses will reveal the pathogenesis of MM induced by somatic mutations, and this model is a useful tool for the development of novel molecular-targeted therapies for MM patients.

The proliferation of PC-3 cells was inhibited by MAZ51 (IC = 2.7 μM) and VEGFR-3 siRNA, and partly decreased by 100 nM GSK690693 (an Akt inhibitor) and 300 nM VEGFR2 Kinase Inhibitor I. MAZ51 and VEGFR-3 siRNA also attenuated the VEGF-C-induced migration of PC-3 cells...These results suggest that VEGFR-3 signaling contributes to the cell proliferation, migration, and tumor growth of androgen-independent/highly metastatic prostate cancer. Therefore, the inhibition of VEGFR-3 has potential as a novel therapeutic target for the treatment for prostate cancer.

P2, N=100, Taiho Oncology, Inc.

To better understand how these drugs exert their therapeutic effects at the molecular level, we combined chemoproteomic target affinity profiling using kinobeads and phosphoproteomics to analyze the five clinical AKT inhibitors AZD5363 (Capivasertib), GSK2110183 (Afuresertib), GSK690693, Ipatasertib, and MK-2206 in BT-474 breast cancer cells. These included CEP170 and FAM83H, suggesting a regulatory function of AKT in mitosis and cytoskeleton organization. In addition, a specific phosphorylation pattern on the ULK1-FIP200-ATG13-VAPB complex was found to determine the active state of ULK1, leading to elevated autophagy in response to AKT inhibition.

TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1 mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

P2, N=96, Recruiting, Taiho Oncology, Inc. | Not yet recruiting --> Recruiting

P2, N=96, Not yet recruiting, Taiho Oncology, Inc.

Inhibitors for PI3K/Akt (GSK690693) and GSK3β (SB415286) confirmed the specificity of rALR treatment for this pathway...Taken all together, rALR might contribute to protecting hepatocytes from toxic concentrations of bile acids by down-regulating their denovo synthesis, attenuating apoptosis by activation of PI3K/Akt - GSK3β pathway and inhibition of JNK signaling. Thereby this suggests a new role of ALR in augmenting the process of liver regeneration.

Here, we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal cancer therapeutics.

ADMET properties of CYP inhibitors obtained from admetSAR 2.0 and were compared with reference drugs for validation. Communicated by Ramaswamy H. Sarma.

Our findings suggest that futibatinib plus TAS-117 has synergistic antitumor effects in FGFR-aberrant tumors. A phase 1/2 study of this combination in advanced solid tumors (JapicCTI-194864) is ongoing.