# Development and Optimization of MNK Inhibitors for the Treatment of Neuropathic Pain

> **NIH NIH U44** · 4E THERAPEUTICS INC. · 2022 · $1,940,921

## Abstract

Abstract
The goal of this project is to develop an optimized MNK inhibitor for neuropathic pain treatment.
MNK is a kinase that phosphorylates eIF4E to control the translation of a distinct subset of
mRNAs. Our focus on this target for neuropathic pain is grounded in evidence that MNK-eIF4E
signaling is activated in nociceptors upon exposure to pain promoting cytokines and growth
factors as well as by peripheral nerve injury, all of which are common factors tied to intractable
neuropathic pain. Importantly, activation of this pathway in nociceptors increases their
excitability, and genetic or pharmacological inhibition of MNK signaling blocks and reverses this
hyperexcitability as well as behavioral signs of neuropathic pain. Critically, treatment of dorsal
root ganglion (DRG) neurons taken from people with neuropathic pain with MNK inhibitors leads
to reversal of nociceptor spontaneous activity, which is thought to be a key driver of neuropathic
pain in patients. MNK inhibitors have been described, but a particular class of molecules, of
which eFT508 (a clinical phase drug for cancer) is the prototype, show strong specificity for
MNK. This molecule will be our starting point for optimization of a new molecule for the
treatment of neuropathic pain. eFT508 requires optimization because MNK inhibition in the
central nervous system (CNS) may lead to depression, an unacceptable side effect for a
neuropathic pain drug. Our group, 4E Therapeutics, plans a targeted medicinal chemistry and
screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment
with the goal of restricting its central nervous system (CNS) penetration while retaining potency,
specificity and in vivo bioavailability and efficacy. In PHASE ONE of this project compounds will
be synthesized and screened against human MNK1 and 2 to assess potency and then will
undergo in vitro ADM and pharmacokinetic (PK) studies in rats to assess plasma to brain drug
concentrations. Compounds that have favorable peripheral PK but lack blood brain barrier
(BBB) penetration will then be tested for in vivo efficacy in neuropathic pain models in rats and
compared directly to eFT508. PHASE TWO will focus on human DRG efficacy and toxicology
studies to verify choice of lead clinical candidate and backup compounds culminating with an
IND-enabled MNK1/2 inhibitor optimized for peripheral neuropathic pain treatment.

## Key facts

- **NIH application ID:** 10469650
- **Project number:** 5U44NS115692-03
- **Recipient organization:** 4E THERAPEUTICS INC.
- **Principal Investigator:** James Jeffrey Sahn
- **Activity code:** U44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,940,921
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469650

## Citation

> US National Institutes of Health, RePORTER application 10469650, Development and Optimization of MNK Inhibitors for the Treatment of Neuropathic Pain (5U44NS115692-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469650. Licensed CC0.

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