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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1U44NS115692-01
Agency Tracking Number: U44NS115692
Amount: $1,551,076.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 104
Solicitation Number: PA18-591
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2019-09-15
Award End Date (Contract End Date): 2021-06-30
Small Business Information
2906 OAKHURST AVE
Austin, TX 78703-1952
United States
DUNS: 038406094
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 JAMES SAHN
 (512) 577-7779
 jim@4etherapeutics.com
Business Contact
 JOSEPH PRICE
Phone: (512) 695-7563
Email: jprice@4etherapeutics.com
Research Institution
N/A
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.Public Health Relevance
The proposed work combines more than a decade of independent development of MNK1/2 as a
neuropathic pain target and medicinal chemistry discovery of potent and specific MNK1/2
inhibitors into an optimization plan with the sole purpose of creating a new type of non-opioid
pain medicine. Given the (1) strong scientific rationale, (2) the existing clinical history of the lead
molecule for optimization, (3) the compelling translational evidence, and (4) the experienced
team, this project has the potential to achieve the ambitious goal of development of an effective,
yet non-addicting treatment for neuropathic pain.

* Information listed above is at the time of submission. *

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