# 4E-BP Mimetics as Chemical Probes for Studying Translational Control in Cancer

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $354,563

## Abstract

Mammalian target of rapamycin complex 1 (mTORC1) signaling is one of the most frequently activated
oncogenic pathways, making it a promising target for cancer drug discovery efforts. Although rapamycin
analogues have been approved for use in select cancers and results from active site mTOR inhibitor clinical
trials have yet to be reported, a new strategy for combatting cancers with hyperactive mTOR signaling is
warranted, particularly since drug resistance to these agents is a growing threat. Our laboratory seeks to
challenge the paradigm of directly targeting mTORC1 or mTOR kinase activity by instead affecting
downstream effectors of mTORC1, namely the eIF4E−4E-BP protein-protein interaction (PPI). These proteins
represent the initiator and gate-keeper, respectively, of cap-dependent mRNA translation, the process by
which oncogenic proteins such as those involved in proliferation, evasion of apoptosis, metastasis and
angiogenesis, the hallmarks of cancer, are produced. This PPI is regulated by mTORC1 via phosphorylation of
4E-BP, which releases eIF4E and stimulates the initiation of cap-dependent translation. Importantly,
maintenance of eIF4E−4E-BP PPI homeostasis has recently been shown to be crucial for mTOR inhibitor
efficacy, and many resistance mechanisms to mTOR inhibitors involve disruption of this balance through
mTORC1-independent 4E-BP phosphorylation, downregulation of 4E-BP, eIF4E amplification, and Myc
overexpression which selectively activates 4E-BP phosphorylation through an unknown mechanism. Thus, we
hypothesize that the eIF4E−4E-BP PPI is a druggable axis in mTOR-hyperactivated cancers and targeting of
this PPI will surmount drug resistance observed with mTOR inhibitors. To probe this hypothesis, we have
rationally designed 4E-BP stapled peptides to act as drug-like 4E-BP mimetics to reactivate the tumor
suppressor activity of 4E-BP and inhibit cancer cell proliferation. In this proposal, we describe our plans to
further develop 4E-BP stapled peptides as chemical probes targeting the eIF4E−4E-BP PPI and fully decipher
their mechanism-of-action through proteomic and cellular analyses. The Specific Aims of this proposal are as
follows: (1) To further develop 4E-BP stapled peptides as chemical probes targeting the eIF4E−4E-BP PPI; (2)
To identify and validate the cellular targets of 4E-BP stapled peptides; and (3) To determine the effect of 4E-
BP stapled peptides in Myc-driven cancer cells. From these proposed studies, we will provide validated
chemical probes for targeting the eIF4E−4E-BP PPI and preliminary data regarding its status as a promising
therapeutic approach for the treatment of cancer.

## Key facts

- **NIH application ID:** 9968095
- **Project number:** 5R01CA202018-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Amanda Garner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968095

## Citation

> US National Institutes of Health, RePORTER application 9968095, 4E-BP Mimetics as Chemical Probes for Studying Translational Control in Cancer (5R01CA202018-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9968095. Licensed CC0.

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