SBIR-STTR Award

Direct to Phase II

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 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:
Pain management; pain treatment; Pain Therapy; Pain Control; inhibitor/antagonist; inhibitor; Antineoplastic Agents; anticancer drug; anticancer agent; anti-cancer drug; Tumor-Specific Treatment Agents; Neoplastic Disease Chemotherapeutic Agents; Cancer Drug; Antineoplastics; Antineoplastic Drugs; Anti-Cancer Agents; Biological Availability; Physiologic Availability; Biologic Availability; Bioavailability; Blood - brain barrier anatomy; Hemato-Encephalic Barrier; Blood-Brain Barrier; Brain; Encephalon; Brain Nervous System; Cell Body; Cells; Pharmaceutic Chemistry; Medicinal Chemistry; Pharmaceutical Chemistry; depression; Mental Depression; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; dorsal root ganglion; Dorsal Root Ganglia; Spinal Ganglia; Goals; History; Recording of previous events; Modern Man; Human; In Vitro; heavy metal lead; heavy metal Pb; Pb element; Lead; leukemia; Medicine; neuronal; Neurocyte; Neural Cell; Nerve Unit; Nerve Cells; Neurons; Nociceptors; Painful; Pain; pain assay; Pain Assessment; Nociception Tests; Analgesia Tests; Pain Measurement; postsurgical pain; post-surgical pain; Post-operative Pain; Postoperative Pain; Patients; Pharmacokinetics; Drug Kinetics; Pharmacology; Protein Phosphorylation; Phosphorylation; Transphosphorylases; Phosphotransferase Gene; Kinases; Phosphotransferases; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Plasma; Proteins; Publishing; Rats Mammals; Rat; Common Rat Strains; Rattus; 5' mRNA Cap Structure; 5' Capped RNA; RNA Caps; mRNA; Messenger RNA; Rodents Mammals; Rodentia; Rodent; biological signal transduction; Signaling; Signal Transduction Systems; Intracellular Communication and Signaling; Cell Signaling; Cell Communication and Signaling; Signal Transduction; Specificity; Toxicology; Translations; General Viruses; Virus; Work; cytokine; RNA-Binding Proteins; chronic pain; base; Peripheral; Area; Clinical; Penetration; Phase; Peripheral Nervous System; Link; non-opioid analgesic; nonopioid; nonopiate analgesic; non-opioid; non-opiate analgesic; non-narcotic analgesic; Nonopioid Analgesics; Nonnarcotic Analgesics; Peripheral nerve injury; Immune response; immunoresponse; host response; Immunological response; Therapeutic; Genetic; Exposure to; Attenuated; long term memory; longterm memory; Ablation; preference; cancer pain; experience; Protein Isoforms; Isoforms; Toxic effect; Toxicities; Structure; Basic Science; Basic Research; Reporting; Mitogen-Activated Protein Kinases; MAP kinase; Extracellular Signal-Regulated Kinases; Neuraxis; Central Nervous System; CNS Nervous System; Pathogenicity; Eukaryotic Initiation Factors; Eukaryotic Translation Initiation Factors; Eukaryotic Peptide Initiation Factors; Molecular Interaction; Binding; MAPK14 gene; p38Alpha; p38-Alpha; p38 Mitogen Activated Protein Kinase; p38 MAPK Gene; p38; Stress-Activated Protein Kinase 2A; SAPK2A; Mxi2; Mitogen-Activated Protein Kinase 14; MAPK14 Mitogen-Activated Protein Kinase; MAPK14; Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2; Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1; CSBP2; CSAID-Binding Protein 2; CSAID-Binding Protein 1; Dose; Symptoms; Data; in vivo; Process; Development; developmental; Behavioral; Pathway interactions; pathway; painful neuropathy; neuropathic pain; cancer type; addiction; addictive disorder; prototype; public health relevance; screening; Growth Factor; Proteins Growth Factors; Growth Substances; Growth Agents; clinical candidate; experimental study; experimental research; experiment; clinical development; pain model; in vivo evaluation; in vivo testing; side effect