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

Njar, V. C. O.; Ramalingam, S.; Ramamurthy, V.; Gediya, L. K.; Murigi, F. N.; Purushottamachar, P.; Huang, W.; Kane, M. A.; Choi, E. Y.; Lapidus, R. G.; Vasaitis, T. S.; Zhang, Y.

doi:10.1101/439208

bioRxiv · 10.1101/439208

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

Njar, V. C. O.·Ramalingam, S.·Ramamurthy, V.·Gediya, L. K.·Murigi, F. N.·Purushottamachar, P.·Huang, W.·Kane, M. A.·Choi, E. Y.·Lapidus, R. G.·Vasaitis, T. S.·Zhang, Y.

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Abstract

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

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Njar, V. C. O., Ramalingam, S., Ramamurthy, V., Gediya, L. K., Murigi, F. N., Purushottamachar, P., Huang, W., Kane, M. A., Choi, E. Y., Lapidus, R. G., Vasaitis, T. S., Zhang, Y.. 2018-10-09. The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis. https://doi.org/10.1101/439208

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