Abstract LB-A20: Novel Dual Oncogenic Target Inhibitor against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K)

Abstract

Abstract The Ras/MEK/ERK and PI3K/Akt/mTor pathways play a central role in the regulation of normal cell growth, division and differentiation. Dysregulation of these signaling pathways driven by oncogenic mutations/activation leading to elevated kinase activity has been demonstrated in many human cancers. Strong evidence suggests the existence of a feedback loop with crosstalk between these two signaling cascades leading to redundancy in survival pathways. Consequently, monotherapy targeting a single cascade may be insufficient to induce tumor cell death due to drug resistance mechanisms. Initial biological results are presented from a series of novel small molecule kinase inhibitors specifically designed to simultaneously target both MEK1 and PI3K. Structural analogs of the ATP-competitive PI3K inhibitor ZSTK474 and the ATP-noncompetitive class of MEK inhibitors PD0325901, respectively, were covalently combined to provide single compound dual inhibitors. Inhibitors showed potent MEK1 inhibition (0.015 < IC50 (nM) < 56.7) and PI3K inhibition (54 < IC50 (nM) < 341) in tumor cell culture inhibition assays. Cellular efficacy studies were accomplished and revealed several of the designed inhibitor analogs demonstrated near complete inhibition of MEK1 and PI3K kinase activity by western blot analysis in A549 lung adenocarcinoma and D54 glioma cell lines at concentrations as low as 5 μM. Inhibitors also produced dose-dependent decreases in cell viability in these cell lines similar to that displayed with the combined administration of equivalent doses of ZSTK474 and PD0325901. In vivo evaluation of selected compounds was undertaken to evaluate oral bioavailability and activity. In preliminary studies conducted in D54 glioma tumor bearing mice, a 95% and 67% inhibition of tumor ERK1/2 and Akt phosphorylation, respectively, was found at 2 h post-administration as determined by western blot analysis. This study reveals that dual targeted small molecules designed to inhibit MEK1/PI3K pathways were effective in target modulation in intact mouse tumor models. Overall, this study details a highly novel approach for combined MEK1/PI3K inhibition with first in vivo results. Citation Format: Brian D. Ross, Hao Hong, Hanxiao Wang, Charles A, Nino, Marcian E. Van Dort. Novel Dual Oncogenic Target Inhibitor against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-A20.