BAY 1143269, a novel MNK1 inhibitor, targets oncogenic protein expression and shows potent anti-tumor activity

Abstract

The initiation of mRNA translation has received increasing attention as an attractive target for cancer treatment in the recent years. The oncogenic eukaryotic translation initiation factor 4E (eIF4E) is the major substrate of MAP kinase-interacting kinase 1 (MNK1), and it is located at the junction of the cancer-associated PI3K and MAPK pathways. The fact that MNK1 is linked to cell transformation and tumorigenesis renders the kinase a promising target for cancer therapy. We identified a novel small molecule MNK1 inhibitor, BAY 1143269, by high-throughput screening and lead optimization. In kinase assays, BAY 1143269 showed potent and selective inhibition of MNK1. By targeting MNK1 activity, BAY 1143269 strongly regulated downstream factors involved in cell cycle regulation, apoptosis, immune response and epithelial-mesenchymal transition in vitro or in vivo. In addition, BAY 1143269 demonstrated strong efficacy in monotherapy in cell line and patient-derived non-small cell lung cancer xenograft models as well as delayed tumor regrowth in combination treatment with standard of care chemotherapeutics. In summary, the inhibition of MNK1 activity with a highly potent and selective inhibitor BAY 1143269 may provide an innovative approach for anti-cancer therapy.

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

“…Our results are also concordant with recent findings by other groups who established that inhibition of eIF4E phosphorylation by Mnk1/2 inhibitors suppressed growth of diffuse large cell B-cell lymphoma and TNBC MDA-MB-231 tumor xenografts (Reich et al, 2018), cell-line and patientderived non-small cell lung cancer xenografts (Santag et al, 2017) and metastasis of KIT-mutant melanoma (Zhan et al, 2017). Furthermore, our finding that VNLG-152R potently suppress the expressions of peIF4E and p4E-BP1 in TNBC in vitro and in vivo is exciting as the 'homogenous expressions' of these oncogenes are proving to be remarkable cancer targets deemed to be more important with respect to therapeutic targeting than the current well-established oncogenic targets such as PI3k, pAkt, pmTOR, pMAPK, HER2, BRCA1/2, AR/AR-Vs and ERα that are 'heterogeneously expressed' in most tumors (Chu et al, 2018;Ramon et al, 2018;Ramon et al, 2014).…”

“…Two recent reports on Mnk1/2 inhibitors (BAY 1143269 inhibits only Mnk1, while eFT508 inhibits both Mnk1 and Mnk2) that are currently under clinical evaluation highlight the significance of Mnk inhibition of pro-tumorigenic cytokines secretions (Reich et al, 2018;Santag et al, 2017). Thus, to enhance the translational potential of VNLG-152R, we conducted head-tohead studies comparing VNLG-152R versus eFT508.…”

Oncogenic MNK signalling regulates the metastasis suppressor NDRG1

“…The very recent development [ 43 ] of an MNK inhibitor which exerts anti-tumour effects in vivo points to the importance of understanding more fully the roles of MNKs in solid tumour biology. This study makes a substantial contribution to achieving that aim.…”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…MNK inhibition leads to a decrease in eIF4E phosphorylation levels, which entails antiproliferative effects, cell cycle arrest and an increase in cellular apoptosis mediated by high levels of cleaved PARP and decreasing MCL-1 (myeloid cell leukemia 1) levels. In addition, MNK inhibition has led to the design of new compounds such as MNKI-8e and 8i, pyrimidine analogs, MNKI-4, MNKI-57, merestinib, cercosporamide, BAY1143269, SEL201or NUCC-54139 [61,62,[92][93][94][95]102,106,[115][116][117][118] (Figure 4).…”

“…All these data reflect that targeting MNK-proteins might be a potential therapeutic strategy for treatment in NSCLC patients. Some MNK inhibitors have been developed in the last few years with satisfactory results such as BAY 1143269 [61], a potent MNK1 inhibitor identified by high-throughput screening. BAY 1143269 is more potent than CGP57380 and cercosporamide, the classical MNK1/MNK2 inhibitors [77,67].…”