Phase II year
2019
(last award dollars: 2022)
Phase II Amount
$4,931,280
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 ofmRNAs. Our focus on this target for neuropathic pain is grounded in evidence that MNK-eIF4Esignaling is activated in nociceptors upon exposure to pain promoting cytokines and growthfactors as well as by peripheral nerve injury, all of which are common factors tied to intractableneuropathic pain. Importantly, activation of this pathway in nociceptors increases theirexcitability, and genetic or pharmacological inhibition of MNK signaling blocks and reverses thishyperexcitability as well as behavioral signs of neuropathic pain. Critically, treatment of dorsalroot ganglion (DRG) neurons taken from people with neuropathic pain with MNK inhibitors leadsto reversal of nociceptor spontaneous activity, which is thought to be a key driver of neuropathicpain in patients. MNK inhibitors have been described, but a particular class of molecules, ofwhich eFT508 (a clinical phase drug for cancer) is the prototype, show strong specificity forMNK. This molecule will be our starting point for optimization of a new molecule for thetreatment of neuropathic pain. eFT508 requires optimization because MNK inhibition in thecentral nervous system (CNS) may lead to depression, an unacceptable side effect for aneuropathic pain drug. Our group, 4E Therapeutics, plans a targeted medicinal chemistry andscreening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatmentwith 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 willbe synthesized and screened against human MNK1 and 2 to assess potency and then willundergo in vitro ADM and pharmacokinetic (PK) studies in rats to assess plasma to brain drugconcentrations. 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 andcompared directly to eFT508. PHASE TWO will focus on human DRG efficacy and toxicologystudies to verify choice of lead clinical candidate and backup compounds culminating with anIND-enabled MNK1/2 inhibitor optimized for peripheral neuropathic pain treatment.
Public Health Relevance Statement: 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.
Project Terms: <5' mRNA Cap Structure><5' Capped RNA> | | |
