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

Ramalingam, Senthilmurugan; Vp, Ramamurthy; Gediya, LK; Fn, Murigi; Purushottamachar, Puranik; Huang, Weiliang; Ey, Choi; Zhang, Yuji; Ts, Vasaitis; Ma, Kane; Rg, Lapidus; Njar, Vincent C.O.

doi:10.1101/439208

Cited by 1 publication

(4 citation statements)

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“…VNLG-152R and the analogs might act as a molecular glue that brings together SYVN1 and MNK1/2 facilitating proximity-induced ubiquitination and subsequent proteasomal degradation as depicted in Figure 9. This study, including our previous studies (9,18,19,33,34), clearly establishes VNLG-152R and its analogs as monomeric molecular glues that induce MNK1 and MNK2 ubiquitin-proteasomal degradation to inhibit oncogenic eIF4F complex.…”

Section: Discussionsupporting

confidence: 64%

“…Among the differentially expressed proteins, SYVN1, an E3 ligase was found to be upregulated threefold in the treated cells (Figure 3A). Based on our previous studies demonstrating the ubiquitin-proteasomal degradation of MNK1/2 induced by VNLG-152R in breast (9,18) and prostate (33, 34) cancer cell lines and the role of SYVN1 as an E3 ligase involved in ubiquitination and proteasomal degradation of several proteins (35)(36)(37)(38)(39)(40)(41)(42), we hypothesized that SYVN1 might play a key role in the ubiquitination and subsequent degradation of MNK1/2. Immunoblotting for SYVN1 confirmed its increased expression in VNLG-152R-treated cells compared to the control with concomitant decrease in MNK1/2 and its product p-eIF4E (Figure 3B).…”

Section: Syvn1 Is Constitutively Upregulated In Vnlg-152r-treated Tnb...mentioning

confidence: 99%

“…Therefore, AR is considered a significant pharmacological target in combating TNBC. However, in the absence of AR in other sub-types such as QNBC, targeting other pathways such as MNK-eIF4E and mTORC1 is more rational (9). Phosphorylation of eIF4E by MNK1/2 is a critical step in mRNA 5'cap-dependent translation of many proteins that actively promote cell division and tumor growth (10).…”

Section: Introductionmentioning

confidence: 99%

“…Previously, we reported the development of a novel MNK1/2 degrader VNLG-152R that promotes degradation of MNK1/2 in breast cancer cells (18) and inhibits TNBC in vivo (9). Additionally, we explored the potential of deuterated derivatives of VNLG-152R, which showed enhanced efficacy against TNBC cells in vitro and improved pharmacokinetic properties in mice models (19).…”

Section: Introductionmentioning

confidence: 99%

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VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2

Thankan,

Thomas,

Purushottamachar

et al. 2023

Front. Oncol.

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Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.

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Section: Discussionsupporting

confidence: 64%