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

Senthilmurugan Ramalingam; Vidya P Ramamurthy; Lalji K Gediya; Francis N Murigi; Puranik Purushottamachar; Weiliang Huang; Eun Yong Choi; Yuji Zhang; Tadas S Vasaitis; Maureen A Kane; Rena G Lapidus; Vincent C O Njar

doi:10.3390/cancers11030299

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

Cancers (Basel). 2019 Mar 3;11(3):299. doi: 10.3390/cancers11030299.

Authors

Senthilmurugan Ramalingam^{1

2}, Vidya P Ramamurthy^{3

4}, Lalji K Gediya^{5

6}, Francis N Murigi^{7

8}, Puranik Purushottamachar^{9

10}, Weiliang Huang¹¹, Eun Yong Choi¹², Yuji Zhang^{13

14}, Tadas S Vasaitis¹⁵, Maureen A Kane¹⁶, Rena G Lapidus¹⁷, Vincent C O Njar^{18

19

20}

Affiliations

¹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. SRamalingam@som.umaryland.edu.
² Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. SRamalingam@som.umaryland.edu.
³ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. rv.darsini@gmail.com.
⁴ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. rv.darsini@gmail.com.
⁵ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. lalji.gediya@gmail.com.
⁶ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. lalji.gediya@gmail.com.
⁷ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. njamurigi@gmail.com.
⁸ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. njamurigi@gmail.com.
⁹ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. PPuranik@som.umaryland.edu.
¹⁰ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. PPuranik@som.umaryland.edu.
¹¹ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201-1559, USA. whuang@rx.umaryland.edu.
¹² Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. echoi@som.umaryland.edu.
¹³ Division of Biostatistics and Bioinformatics, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201-1559, USA. Yuzhang@som.umaryland.edu.
¹⁴ Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Yuzhang@som.umaryland.edu.
¹⁵ Department of Pharmaceutical Sciences, School of Pharmacy and Health Professions, University of Maryland Eastern Shore, 207 Somerset Hall, Princess Anne, MD 21853, USA. tsvasaitis@umes.edu.
¹⁶ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201-1559, USA. mkane@rx.umaryland.edu.
¹⁷ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. rlapidus@som.umaryland.edu.
¹⁸ Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.
¹⁹ Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.
²⁰ Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA. vnjar@som.umaryland.edu.

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, racemic VNLG-152R and its two enantiomers (VNLG-152E1 and VNLG-152E2) in in vitro and in vivo models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader, superior to its pure enantiomers. 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 (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) 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 the effective treatment of patients with primary/metastatic TNBC.

Keywords: Mnk-eIF4E/mTORC1 signaling pathways; Mnk1/2 degraders; VNLG-152R; apoptosis; metastasis; triple negative breast cancer.

Abstract

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