Compositions and methods for treating pain disorders

Abstract

Provided are methods to treat, ameliorate, prevent, reverse, decrease the severity and / or duration of a pain-associated disease or condition comprising administration of a pharmaceutically acceptable formulation comprising a glycolysis inhibitor.

Description

Docket No. EPN-AC-RAFT.004PC PATENT COMPOSITIONS AND METHODS FOR TREATING PAIN DISORDERS GOVERNMENT RIGHTS 5

[0001] This invention was made with US government support under grants NS102432 and awarded by the National Institutes of Health (NIH). The US government has certain rights in the invention. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This International Patent Application claims the benefit of priority to pending US 10 Provisional Patent Application Ser. No.63 / 703,934, filed October 5, 2024, the contents of which are incorporated herein in its entirety. TECHNICAL FIELD

[0003] This invention generally relates to medicine, inflammation, pain control and cell biology. In particular, provided herein are methods to treat, ameliorate, prevent, reverse, 15 decrease the severity and / or duration of a pain-associated disease or condition including but not limited to a neuropathic pain, a CNS inflammation, an allodynia, a post nerve injury pain, a post-surgical pain, a hyperalgesia, and primary headaches such as migraines and cluster headaches by administering to a subject in need thereof of a pharmaceutically acceptable formulation comprising an inhibitor of cellular glycolysis, in particular an 20 inhibitor of 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3 (PFKFB3), or an inhibitor of Insulin-like growth factor 1 receptor (IGF1R) signaling as described herein. BACKGROUND OF THE INVENTION

[0004] Medical conditions where pain is a major symptom of disease remains a significant problem to healthcare. By example, soft tissue or orthopedic surgeries, leads to 25 upwards of 80-90% of patients experiencing pain requiring aggressive interventions for intervals up to 2-4 days, with 40-60% showing symptoms at intervals of 5-9 days (Brattwell 2011, Tran 2015). Smaller populations may experience pain yet longer for periods greater than 3 months (Krakowski 2021). Migraine is a primary headache disorder, affecting one in nine adults worldwide (Stovner 2007). The Global Burden of 30 Disease 2016 study ranks migraine as second in terms of years lived with disability,Docket No. EPN-AC-RAFT.004PC PATENT particularly in young adult and middle-aged women and sixth leading cause for men of all ages (Vetvik 2017). With such prevalence in patient populations and deficiencies in existing medications, new pharmacotherapies are necessary to manage pain-associated diseases and conditions. 5 SUMMARY OF THE INVENTION

[0005] In a principal aspect of the invention, provided are compositions and methods and uses for treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition of a subject wherein the disease or condition is selected from the group consisting of: 10

[0006] - neuropathic pain,

[0007] - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain,- nerve or CNS inflammation, 15 wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation,

[0008] - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia,

[0009] - a post nerve or tissue injury pain or neuropathic pain, 20 wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma,

[0010] - post-surgical pain or neuropathic pain,

[0011] - chemotherapy-induced neuropathic pain

[0012] - a primary headache, wherein is some aspects is a migraine or a cluster headache, 25 and

[0013] - hyperalgesia,

[0014] wherein the method comprises administering to the subject:

[0015] (a) a pharmaceutically acceptable formulation comprising at least one pharmaceutically acceptable excipient and:Docket No. EPN-AC-RAFT.004PC PATENT

[0016] an inhibitor of cellular glycolysis, in particular an inhibitor of 6-phosphofructo-2- kinase / fructose-2,6-biphosphatase 3 (PFKFB3), or an inhibitor of Insulin-like growth factor 1 receptor (IGF1R) signaling; and wherein said administering is by intranasal, intrathecal, oral, or parenteral 5 administration, thereby treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition of a subject wherein the disease or condition is selected from the group consisting of:

[0017] - neuropathic pain, 10

[0018] - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain,

[0019] - nerve or CNS inflammation, wherein in some aspects the nerve or CNS inflammation comprises a TLR4- 15 mediated nerve or CNS inflammation,

[0020] - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia,

[0021] - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is 20 generated or caused by, or is a sequela to, trauma,

[0022] - post-surgical pain or neuropathic pain,

[0023] - chemotherapy-induced neuropathic pain

[0024] - a primary headache, wherein is some aspects is a migraine or a cluster headache, and 25

[0025] - hyperalgesia.

[0026] In some preferred aspects, administration is by the intrathecal route.

[0027] In other preferred aspects, administration is by the nasal route.

[0028] In other preferred aspects, administration is by the parenteral route.

[0029] In still other preferred aspects, administration is by the oral route. 30

[0030] In other alternative principal aspects of the invention, provided are uses of a pharmaceutically acceptable formulation as provided herein, in the manufacture of a medicament.Docket No. EPN-AC-RAFT.004PC PATENT

[0031] In still other alternative principal aspects of the invention, provided are uses of a pharmaceutically acceptable formulation as provided herein, in the manufacture of a medicament for treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition of a subject 5 wherein the disease or condition is selected from the group consisting of:

[0032] - neuropathic pain,

[0033] - inflammation-induced neuropathic pain, wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, 10

[0034] - nerve or CNS inflammation, wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation,

[0035] - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, 15

[0036] - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma,

[0037] - post-surgical pain or neuropathic pain,

[0038] - chemotherapy-induced neuropathic pain 20

[0039] - a primary headache, wherein in some aspects isa migraine or a cluster headache, and

[0040] - hyperalgesia.

[0041] In alternative aspects, provided are a pharmaceutically acceptable formulation as described herein, or a therapeutic combination comprising said formulation, for treating, 25 ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of:

[0042] - neuropathic pain,

[0043] - inflammation-induced neuropathic pain, 30 wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain,

[0044] - nerve or CNS inflammation,Docket No. EPN-AC-RAFT.004PC PATENT wherein in some aspects the nerve or CNS inflammation comprises a TLR4- mediated nerve or CNS inflammation,

[0045] - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia, 5

[0046] - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is generated or caused by, or is a sequela to, trauma,

[0047] - post-surgical pain or neuropathic pain,

[0048] - chemotherapy-induced neuropathic pain, 10

[0049] - a primary headache, wherein in some aspects a migraine or a cluster headache, and- hyperalgesia,

[0050] wherein the pharmaceutically acceptable formulation or the therapeutic combination is intended for oral administration to the subject.

[0051] The details of one or more embodiments of the invention are set forth in the 15 accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The drawings set forth herein are illustrative of embodiments provided herein and 20 are not meant to limit the scope of the invention.

[0053] Figure 1 schematically illustrates the upregulation of cellular glycolysis following the development of lipid “inflammarafts” associated with neuroinflammation and spinal pain signaling. Blockade of glycolysis pathways leads to disruption of inflammaraft signaling and the alleviation of pain. 25

[0054] Figure 2 illustrates the alleviation of pain by inhibitors of cellular glycolysis in a mouse model of chemotherapy induced peripheral neuropathy (CIPN). Wild type mice received intraperitoneal (i.p.) saline (naive group) or cisplatin (two injections of 2.3 mg / kg / day: CIPN). CIPN groups received intrathecal (i.t.) injection of 3PO (1.75 µg / 5µL: CIPN+3PO), or a neutralizing anti-IGF1R antibody (0.25 µg / 5µL: CIPN+IGF1RAb), IgG 30 control (0.25 µg / 5µL) or vehicle (12.6% PBS in saline) were included. Following a single administration of either inhibitor, reversal of tactile thresholds was observed over a period of 14 days post treatment.Docket No. EPN-AC-RAFT.004PC PATENT

[0055] Figure 3 illustrates the disruption of lipid “inflammarafts” on spinal microglia of cellular glycolysis inhibitors in the same CIPN animal model (FIG.2).3PO affords statistically significant changes in TLR4 associated with spinal microglia (A), normalization of TLR4 dimers relative to control (B) and a trend to lipid raft reduction 5 (C). IGF1R antibody showed a trend to reduction in these parameters. Flow cytometry analysis of CD11b+ / TMEM119+ spinal microglia cells showing A: TLR4 proximity to lipid rafts (CTB) by PLA (proximity ligation assay) signal. B: TLR4 dimers, and C. lipid raft content measured by CTB staining, in spinal microglia from same animals euthanized on day 21. 10

[0056] Figures 4 and 5 illustrate inhibitors of glucose transporter 1 (GLUT 1).

[0057] Figures 6, 7 and 8 illustrate inhibitors of hexokinase.

[0058] Figures 9, 10, 11, 12, 13, 14, 15 and 16 illustrate inhibitors 6-phosphofructo-2- kinase / fructose-2,6-biphosphatase 3 (PFKFB3).

[0059] Figures 17 and 18 illustrate inhibitors of pyruvate kinase. 15

[0060] Figures 19 and 20 illustrate inhibitors of lactate dehydrogenase.

[0061] Figures 21, 22, 23 and 24 illustrate inhibitors of Insulin-like growth factor 1 receptor (IGF1R) signaling.

[0062] Like reference symbols in the various drawings indicate like elements.

[0063] Reference is now made in detail to various exemplary embodiments provided 20 herein, examples of which are illustrated in the accompanying drawings. The following detailed description is provided to give the reader a better understanding of certain details of aspects and embodiments of the invention, and should not be interpreted as a limitation on the scope of the invention. DETAILED DESCRIPTION 25

[0064] Provided are pharmaceutically acceptable compositions as described herein, or a therapeutic combination comprising said formulation, for treating, ameliorating, preventing, reversing or decreasing the severity or duration of, or decreasing the severity of symptoms of a disease or condition in a subject, wherein the disease or condition is selected from the group consisting of: 30

[0065] - neuropathic pain,

[0066] - inflammation-induced neuropathic pain,Docket No. EPN-AC-RAFT.004PC PATENT wherein in some aspects the inflammation-induced neuropathic pain comprises a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain,

[0067] - nerve or CNS inflammation, wherein in some aspects the nerve or CNS inflammation comprises a TLR4- 5 mediated nerve or CNS inflammation,

[0068] - allodynia, wherein in some aspects the allodynia comprises a TLR4-mediated allodynia,

[0069] - a post nerve or tissue injury pain or neuropathic pain, wherein in some aspects the post nerve or tissue injury pain or neuropathic pain is 10 generated or caused by, or is a sequela to, trauma,

[0070] - post-surgical pain or neuropathic pain,

[0071] -chemotherapy-induced neuropathic pain

[0072] - a primary headache, wherein is some aspects the primary headache is a migraine or a cluster headache, 15 and

[0073] - hyperalgesia.

[0074] A principal aspect of this invention are compositions containing one or more compounds that are inhibitors of cellular glycolysis that modulate the presence of inflammarafts, which are enlarged, cholesterol-enriched lipid rafts that organize the 20 inflammatory response during neuroinflammation and the development of pain.

[0075] In certain aspects, the glycolysis inhibitor is administered in a pharmaceutically acceptable formulation, wherein administration is either by the intranasal, intrathecal, oral, or parenteral routes.

[0076] In certain aspects administration is by the intrathecal route. 25

[0077] In other aspects, administration is by the parenteral route.

[0078] In other preferred aspects that include intravenous or subcutaneous delivery.

[0079] In still other preferred aspects, administration is by the intranasal or oral routes. DEFINITIONS

[0080] “Cellular glycolysis” as used herein is a metabolic process that occurs in the 30 cytoplasm of a cell to break down glucose and produce energy. Glycolysis is a set of reactions that converts glucose to pyruvate or lactate and represents a pathway inDocket No. EPN-AC-RAFT.004PC PATENT utilization of glucose for energy in the cell. Glycolysis is also referred to as the Embden- Meyerhoff pathway.

[0081] “Cellular glycolysis inhibitor” as used herein refers to compounds disclosed that block the cellular production of pyruvate or lactate by interaction with cellular glycolysis 5 referred to as the Embden-Meyerhoff pathway.

[0082] “Primary headaches” are headaches that don't have an identifiable cause and are instead caused by issues with pain-sensitive structures in the head.

[0083] "Pharmaceutically acceptable formulation” as used herein means a composition comprising an active pharmaceutical ingredient, such as compounds described herein in 10 addition to one or more pharmaceutically acceptable excipient or refers to an active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients,

[0084] wherein the composition is suitable for administration to a subject, such as a human or an animal, in need thereof. For a pharmaceutically acceptable formulation to be suitable for administration to a human the formulation must have biological activity for 15 treating or preventing a disease or condition disclosed herein or an expectation must exist that the formulation would have a desired activity towards an "intent to treat" disease or condition.

[0085] Typically, the "intent to treat” disease or condition is neuropathic pain, inflammation-induced neuropathic pain, a Toll-like receptor 4 (TLR4)-mediated 20 inflammation-induced neuropathic pain, nerve or CNS inflammation, a TLR4-mediated nerve or CNS inflammation, allodynia, a TLR4-mediated allodynia, a post nerve or tissue injury pain or neuropathic pain, a post nerve or tissue injury pain or neuropathic pain generated or caused by, or is a sequela to, trauma, a post-surgical pain or neuropathic pain, chemotherapy-induced neuropathic pain, a primary headache, wherein is some 25 aspects is a migraine or a cluster headache, and hyperalgesia.

[0086] A pharmaceutically acceptable formulation that is suitable for administration to an animal does not necessarily require a biological activity for treating or preventing a disease or condition, and in some embodiments is administered to the animal in order to evaluate a potential pharmacological or biological activity of compounds disclosed 30 herein. Those formulations must therefore be suitable for treating or preventing a disease or condition disclosed herein in an animal in need thereof or is suitable for evaluating a pharmacological or biological activity compounds disclosed herein. Compositions that are suitable only for use in vitro essays or which contain a vehicle, component or excipient inDocket No. EPN-AC-RAFT.004PC PATENT an amount not permitted in a drug product are specifically excluded from the definition of a pharmaceutically acceptable formulation.

[0087] The pharmaceutically acceptable formulation in some embodiments is comprised of, or be prepared from one, two or more compounds disclosed herein, typically one or 5 two, and one or more pharmaceutically acceptable excipients. More typically, the formulations will consist essentially of or consist of a single compound disclosed herein and one or more pharmaceutically acceptable excipients.

[0088] Other formulations in some embodiments are comprised of, consist essentially of, or consist of one, two or more compounds disclosed herein and one, two or more 10 compounds in current use for treating neuropathic pain, inflammation-induced neuropathic pain, a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, nerve or CNS inflammation, a TLR4-mediated nerve or CNS inflammation, allodynia, a TLR4-mediated allodynia, a post nerve or tissue injury pain or neuropathic pain, a post nerve or tissue injury pain or neuropathic pain generated or 15 caused by, or is a sequela to, trauma, a post-surgical pain or neuropathic pain, chemotherapy-induced neuropathic pain, a primary headache, wherein is some aspects is a migraine or a cluster headache, and hyperalgesia, and one or more pharmaceutically acceptable excipients.

[0089] Typically, those formulations will consist essentially of or consist of a single20 compound, a single compound in current use for treating neuropathic pain, inflammation- induced neuropathic pain, a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, nerve or CNS inflammation, a TLR4-mediated nerve or CNS inflammation, allodynia, a TLR4-mediated allodynia, a post nerve or tissue injury pain or neuropathic pain, a post nerve or tissue injury pain or neuropathic pain generated or25 caused by, or is a sequela to, trauma, a post-surgical pain or neuropathic pain, - chemotherapy-induced neuropathic pain, a primary headache, wherein is some aspects is a migraine or a cluster headache, and hyperalgesia, and one or more pharmaceutically acceptable excipients.

[0090] "Solid formulation" as used herein refers to a pharmaceutically acceptable 30 formulation comprising at least one of the compounds disclosed herein and one or more pharmaceutically acceptable excipients in solid form(s) wherein the formulation is in a unit dosage form suitable for administration of a solid. The dosage units include tablet~.Docket No. EPN-AC-RAFT.004PC PATENT capsules. caplets, gelcaps, suspensions and other dosage units typically associated with parenteral or enteral (oral) administration of a solid.

[0091] "Liquid formulation" as used herein refers to a pharmaceutically acceptable formulation wherein at least one of the compounds described herein has been mixed or 5 contacted with one or more pharmaceutically acceptable excipients, wherein at least one of the excipients is in liquid form in proportions required for a liquid formulation, i.e., such that a majority of the mass amount of the compound(s) described herein is dissolved into the non-solid excipient. Dosage units containing a liquid formulation include syrups, gels, ointments and other dosage units typically associated with intrathecal, parenteral or 10 enteral administration of a pharmaceutical formulation to a subject in need thereof in liquid form.

[0092] “Nasal formulation” as used herein refers to nasal spray formulations that may be water-based, hydroalcoholic, nonaqueous, suspensions, or emulsions. A formulation typically includes one or more diverse pharmaceutically acceptable excipients, including 15 solvents, mucoadhesive agents, buffers, antioxidants, preservatives, and penetration enhancers (i.e., compounds to improve absorption or penetration).

[0093] "Prevent, “preventing" and like terms as used herein takes on its normal and customary meaning in the medical arts and so therefore does not require that each instance to which the term refers be avoided with certainty. 20 NUMBERED EMBODIMENTS

[0094] The following embodiments exemplify the invention but are not meant to limit said invention in any manner. In certain embodiments this invention describes the surprising finding that inhibitors of cellular glycolysis demonstrate profound and long- lasting amelioration of pain associated with chemotherapy induced peripheral neuropathy 25 (CIPN).

[0095] Embodiment 1. A method of treatment or prevention of pain with an inhibitor of cellular glycolysis wherein the pain is neuropathic pain, inflammation-induced neuropathic pain, a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, nerve or CNS inflammation, a TLR4-mediated nerve or CNS 30 inflammation, allodynia, a TLR4-mediated allodynia, a post nerve or tissue injury pain or neuropathic pain, a post nerve or tissue injury pain or neuropathic pain generated or caused by, or is a sequela to, trauma, a post-surgical pain or neuropathic pain,Docket No. EPN-AC-RAFT.004PC PATENT chemotherapy-induced neuropathic pain, a primary headache, wherein is some aspects is a migraine or a cluster headache, and hyperalgesia, wherein the cellular glycolysis inhibitor comprises a therapeutically effective amount of said glycolysis inhibitor administered in a pharmaceutically acceptable formulation, wherein administration is 5 either by the intranasal, intrathecal, oral, or parenteral routes.

[0096] Embodiment 2. The method of embodiment 1 wherein the glycolysis inhibitor is an inhibitor of any one of the components of the cellular glycolysis pathway or a protein shown to regulate the cellular glycolysis pathway.

[0097] Embodiment 3. The method of embodiment 2 wherein the glycolysis inhibitor is10 an inhibitor of the glucose transporter 1 (GLUT 1), Hexokinase, 6-phosphofructo-2- kinase / fructose-2,6-biphosphatase 3 (PFKFB3), pyruvate dehydrogenase kinase (PDHK), lactate dehydrogenase, or an inhibitor of Insulin-like growth factor 1 receptor (IGF1R) signaling.

[0098] Embodiment 4. The method of embodiment 3 wherein the glycolysis inhibitor is a 15 GLUT 1 inhibitor.

[0099] Embodiment 5. The method of embodiment 4 wherein the GLUT 1 inhibitor is an antibody or antigen-binding antibody fragment (e.g., a single chain antibody, a single- domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, triabody, 20 tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), a peptibody, a nanobody, a GLUT 1 binding polypeptide, peptoid, or a small molecule GLUT 1 inhibitor.

[0100] Embodiment 6. The method of embodiment 5 wherein the peptoid GLUT 1 25 inhibitor has the structure of ritonavir and is displayed in Fig 4.

[0101] Embodiment 7. The method of embodiment 4 or 5 wherein the small molecule GLUT 1 inhibitor is selected from the group consisting of Cytochalesin B, Phloretin (3- (p-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-1-propanone), Quercetin (2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4-chromenone), Genistein (5,7-dihydroxy-3-(p-30 hydroxyphenyl)-4-chromenone), Apigenin (5,7-dihydroxy-2-(p-hydroxyphenyl)-4- chromenone), Silibenin ( 2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2- (hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5,7-trihydroxy-4-chromenone), PUG-1 (8-[(S)-1-hydroxyethyl]-1,7-dihydro-6-purinone), Chromopynone 1 (N-[2-(p-Docket No. EPN-AC-RAFT.004PC PATENT tolyl)ethyl]m-{(1R,9R)-6-ethoxy-9-methyl-11-oxo-8-oxa-10,12- diazatricyclo[7.3.1.02,7]trideca-2,4,6-trien-10-yl}benzamide), Fasentin (N-[4-chloro-3- (trifluoromethyl)phenyl]acetoacetamide), Trehalose ( (2R,3R,4S,5S,6R)-2- [(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]-6- 5 (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol), WZB117 (2-fluoro-6-(m- hydroxybenzoyloxy)phenyl m-hydroxybenzoate), STF31 (N-3-pyridylp-[p-(tert- butyl)phenylsulfonylamino]benzamide, Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3- methoxyphenyl)-1,6-heptadiene-3,5-dione), BAY-876 (N-{1-[(p-cyanophenyl)methyl]-5- methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2-[(aminooxy)methyl]-7-fluoro-4- 10 quinolinecarboxamide and salts thereof, structures of which are displayed in Fig 5.

[0102] Embodiment 8. The method of embodiment 3 wherein the glycolysis inhibitor is a hexokinase inhibitor.

[0103] Embodiment 9. The method of embodiment 8 wherein the hexokinase inhibitor is an antibody or antigen-binding antibody fragment (e.g., a single chain antibody, a 15 single-domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, triabody, tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), a peptibody, a nanobody, a hexokinase binding polypeptide such as 20 hexokinase II VDAC binding domain peptide, or a small molecule hexokinase inhibitor.

[0104] Embodiment 10. The method of embodiment 8 or 9 wherein the small molecule hexokinase inhibitor is selected from the group consisting of 2-deoxy-d-glucose (2-DG), 3-bromopyruvate (3-BrPA), metformin (3-(Azanylazanylidenemethyl)-1,1-25 dimethylguanidine), hexokinase 2 inhibitor 1 ([(E)-3-(2,3,4-trihydroxyphenyl)-2-triazen- 1-yl](p-nitrophenyl)methanone, lonidamine (1-[(2,4-dichlorophenyl)methyl]-1H- indazole-3-carboxylic acid), metrizamide (N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-3-yl]-1,3-bis(N-methylacetylamino)-2,4,6-triiodo- 5-benzamide, benitrobenrazide ((E)-2-[(2,3,4-trihydroxyphenyl)methylene]hydrazino}(p-30 nitrophenyl)methanone, benserazide (2-amino-3-hydroxy-1-{2-[(2,3,4- trihydroxyphenyl)methyl]hydrazino}-1-propanone), Oroxylin A (5,7-dihydroxy-6- methoxy-2-phenyl-4-chromanone), Chrysin (5,7-dihydroxy-2-phenyl-4-chromanone), resveratrol ((E)-3,5,10-stilbenetriol), fenofibrate (methyl 2-[p-(p-Docket No. EPN-AC-RAFT.004PC PATENT chlorobenzoyl)phenoxy]-2-methylpropionate), GL-V9 (5-hydroxy-8-methoxy-2-phenyl- 7-[4-(1-pyrrolidinyl)butoxy]-4-chromanone), Gen-27 (5-hydroxy-7-(2-hydroxy-3- piperidinopropoxy)-3-[p-(2-hydroxy-3-piperidinopropoxy)phenyl]-4-chromanone), and salts thereof, which have the structures shown in FIG 6. 5

[0105] Embodiment 11. The method of embodiment 8 or 9 wherein the small molecule hexokinase inhibitor is selected from the group consisting of Amentoflavone (8-[5-(5,7- dihydroxy-4-oxo-2-chromanyl)-2-hydroxyphenyl]-5,7-dihydroxy-2-(p-hydroxyphenyl)-4- chromenone), MJ ( methyl {2-[(E)-2-pentenyl]-3-oxocyclopentyl}acetate), bufalin (5- {(1S,2S,5S,7R,10R,11R,14R,15R)-5,11-dihydroxy-2,15-dimethyltetracyclo-10 [8.7.0.02,7.011,15]heptadec-14-yl}-2-pyranone), cryptotanshinone ((R,11(15)E)-6,6,14- trimethyl-12-oxatetracyclo[8.7.0.02,7.011,15]heptadeca-1,7,9,11(15)-tetraene-16,17-dione), halofuginone (3-{3-[(2R,3S)-3-hydroxy-2-piperidyl]-2-oxopropyl}-7-bromo-6-chloro- 3H-quinazolin-4-one), licochalcone A ((E)-3-[5-(1,1-dimethyl-2-propenyl)-4-hydroxy-2- methoxyphenyl]-1-(p-hydroxyphenyl)-2-propen-1-one), jolkinolide B 15 ((1S,3R,8R,10R,11R,12R,17R)-5,12,16,16-tetramethyl-2,7,9-trioxahexacyclo- [9.8.0.01,3.04,8.08,10.012,17]nonadec-4-en-6-one), ORY-1001 ((1r,4r)-1-[(1R,2S)-2- phenylcyclopropylamino]-4-aminocyclohexane, ginsenoside 20(S)-Rg3 ((2R,3S,4S,5R,6R)-6-{(2R,5S,7R,10R,14S,15S,16R)-16-hydroxy-14-(1-hydroxy-1,5- dimethyl-4-hexenyl)-2,6,6,10,11-pentamethyltetracyclo[8.7.0.02,7.011,15]heptadec-5-20 yloxy}-5-[(2S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yloxy]-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol), 6913-0012 (ethyl 5-{(R)-3-[(R)- 1-(hydroxymethyl)propylamino]-2-methylpropoxy}-1-methyl-2-methyl-1H-indole-3- carboxylate), and salts thereof, which have the structures shown in FIG 7.

[0106] Embodiment 12. The method of embodiment 8 or 9 wherein the small molecule25 hexokinase inhibitor is selected from the group consisting of K263-0793 (N-3,4- dihydroxyphenyl (1-oxo-2-[(3-pyridyl)methyl]-2H-9-thia-2,4-diazafluoren-3- ylthio}acetamide), K611-0094 (N-(1,3-thiazol-2-yl)-2-[(N-m-nitrophenylcarbamoyl)- methylthio]-4-amino-1,3-thiazole-5-carboxamide), D016-0099 (1-{5-[(S)-2-hydroxy-3- (phenethylamino)propoxy]-2-methyl-1H-indol-3-yl}-1-ethanone), K788-8853 (N-{[(S)-1-30 ethyl-2-pyrrolidinyl]methyl}-(E)-2-[(3,4-dimethoxyphenyl)methylene]-3-oxo-4H-1,4- benzothiazine-6-carboxamide), 4244-3659 ((S)-3-[(2,5-dihydroxybenzoyl)methyl]-3- hydroxy-1-methyl-2-indolinone), AK-968 / 41922716 ({(E)-2-[(3,4-dichlorophenyl)- methylene]hydrazino}(3,4,5-trihydroxyphenyl)methanone), AO-423 / 13128074 ((R)-3-Docket No. EPN-AC-RAFT.004PC PATENT benzylamino-1-(1-naphthyloxy)-2-propanol), AP-124 / 43383769 ((R)-3-benzylamino-1- (2-isopropyl-5-methylphenoxy)-2-propanol), and salts thereof, which have the structures shown in FIG 8.

[0107] Embodiment 13. The method of embodiment 3 wherein he glycolysis inhibitor is a 5 6-phosphofructo-2-kinase / fructose-2,6-biphosphatase 3 (PFKFB3) inhibitor.

[0108] Embodiment 14. The method of embodiment 13 wherein the PFKFB3 inhibitor is an antibody or antigen-binding antibody fragment (e.g., a single chain antibody, a single-domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, 10 triabody, tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), a peptibody, a nanobody, a PFKFB3 binding polypeptide or peptide, or a small molecule PFKFB3 inhibitor.

[0109] Embodiment 15. The method of embodiment 13 or 14 wherein the peptide15 PFKFB3 inhibitor is selected from the group consisting of P1 ((S)-2-[(S)-2-[(S)-2- {(S)-2-[(S)-2-Amino-3-hydroxypropionylamino]-3-phenylpropionylamino}-4- methylvalerylamino]-4-methylvalerylamino]-6-amidinohexanamide), P2 ((R)-2- ({[(R)-2-Amino-3-(1H-indol-3-yl)propionylamino]methyl}carbonylamino)-3-(p- hydroxyphenyl)propionic acid), P3 ((2S,3R)-2-[(S)-2-[(S)-2-[({(S)-2-[(S)-2-Amino-20 3-(p-hydroxyphenyl)propionylamino]-3-hydroxypropionylamino}methyl)- carbonylamino]-3-phenylpropionylamino]-4-methylvalerylamino]-3-hydroxybutyric acid), and salts thereof, the structures of which are shown in FIG 9.

[0110] Embodiment 16. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of BrAcNHEtOP25 (N-bromoacetylethanolamine phosphate), 3-PO (3-(3- pyridinyl)-1-(4-pyridinyl)-2- propen-1-one), PFK15 (l-(4- pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), or PFK- 158 ((E)-1-(4-Pyridinyl)-3- [7-(trifluoromethyl)-2-quinolinyl]-2-propen-1-one), PQP ((E)-1-(3-pyridyl)-3-(2-quinolyl)-2-propen-1-one) and salts thereof.

[0111] Embodiment 17. The method of embodiment 13 or 14 wherein the small 30 molecule PFKFB3 inhibitor is selected from the group consisting of KAN0436151 (4-[5-Chloro-4-(m-fluorophenyl)-2-thienylsulfonylamino]-2-hydroxybenzoic acid), KAN0436067 (m-(5-isopropyl-3-methyl-1-benzothiophen-2-ylsulfonylamino)- benzoic acid), KAN0438757 (2-hydroxyethyl 4-(5'-fluoro-2'-hydroxy-3-Docket No. EPN-AC-RAFT.004PC PATENT biphenylylsulfonylamino)-2-hydroxybenzoate), or a salt thereof; N4A (5,6,7,8- Tetrahydroxy-2-(p-hydroxyphenyl)-4-chromanone), YNl (7,8-Dihydroxy-3-(p- hydroxyphenyl)-4-chromanone), YZ29 (ethyl 7-hydroxy-3-coumarincarboxylate), and salts thereof, the structures of which are shown in FIG 10. 5

[0112] Embodiment 18. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of AZ11 (N-[p-(2- amino-3-cyano-1-methyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ44 (N-[p- (2-amino-3-cyano-1H-indol-5-yloxy)phenyl](S)-2-amino-3-hydroxypropionamide), AZ46 (N-[p-(2-amino-3-cyano-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ47 10 (N-[p-(2-amino-3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ48 (N-[p-(2-amino-3-cyano-1-isobutyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ49 (N-[p-(2-Amino-1-benzyl-3-cyano-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ50 (N,N-dimethyl[2-amino-3-cyano-5-(p-glycylaminophenoxy)-1H-indol-1- yl]acetamide), AZ51 (N-[p-(3-cyano-1H-indol-5-yloxy)phenyl]aminoacetamide),15 AZ52 (N-[p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ53 (N- [p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl](methylamino)acetamide), AZ54 (N- [p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl](dimethylamino)acetamide, AZ55 (N- [p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), and salts thereof, the structures of which are shown in FIG 11. 20

[0113] Embodiment 19. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of AZ56 (N-[p-(3- cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(R)-2-pyrrolidinecarboxamide), AZ57 (N- [p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-N-methyl-(S)-2- pyrrolidinecarboxamide), AZ58 (N-[p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-25 (S)-2-azetidinecarboxamide), AZ59 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl]-(S)-2-piperidinecarboxamide), AZ60 (N-[p-(3-cyano-1-ethyl-1H- indol-5-yloxy)phenyl]-(S)-5-oxo-2-pyrrolidinecarboxamide), AZ61 (N-(p-{1-[(N- methylcarbamoyl)methyl]-3-cyano-1H-indol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ62 (N-(p-{3-cyano-1-[2-(dimethylamino)ethyl]-1H-30 indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide), AZ63 (N-(p-{3-cyano-1- [(tetrahydro-2H-pyran-4-yl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ64 (N-[p-(3-cyano-1-phenyl-1H-indol-5-yloxy)phenyl]- (S)-2-pyrrolidinecarboxamide), AZ65 (N-{p-[3-cyano-1-(2-methyl-1-oxo-5-Docket No. EPN-AC-RAFT.004PC PATENT isoindolinyl)-1H-indol-5-yloxy]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ66 (N-[p- (1-benzyl-3-cyano-1H-indol-5-yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ67 (N-(p-{3-cyano-1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H-indol-5-yloxy}phenyl)- (S)-2-pyrrolidinecarboxamide), and salts thereof, the structures of which are 5 displayed in FIG 12.

[0114] Embodiment 20. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of AZ26 (N-[p-(3- Cyano-1-isobutyl-1H-indol-5-yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ33 (N-(p-{3-cyano-1-[(3,5-dimethyl-4-isoxazolyl)methyl]-1H-indazol-5-yloxy}phenyl)-10 (S)-2-pyrrolidinecarboxamide), AZ68 (N-[p-(3-cyano-1-isobutyl-1H-indazol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ69 (N-{p-[3-(1-methyl-1H- pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}aminoacetamide), AZ40 (N-{p-[3-(1-methyl- 1H-pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ43 (N-{p-[1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}-(S)-2-15 pyrrolidinecarboxamide), AZ70 (N-[p-(3-cyano-1-isobutyl-1H-indol-5- ylamino)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ71 (N-{p-[(3-cyano-1-isobutyl- 1H-indol-5-yl)-N-methylamino]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ72 (N-[p- (3-cyano-1-isobutyl-1H-indol-5-ylthio)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ73 (N-[p-(3-cyano-1-isobutyl-1H-indol-5-ylsulfonyl)phenyl]-(S)-2-20 pyrrolidinecarboxamide), AZ74 (N-{p-[(3-Cyano-1-isobutyl-1H-indol-5- yl)methyl]phenyl}-(S)-2-pyrrolidinecarboxamide), and salts thereof, the structures of which are shown in FIG 13.

[0115] Embodiment 21. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of the structures of25 formula 1(4-[4-(2H-1,3-benzodioxol-5-yl)-5-chloro-2-thienylsulfonylamino]-2- hydroxybenzoic acid), formula 2 (2-Hydroxy-4-[m-(6-quinolyl)phenylsulfonyl- amino]benzoic acid), formula 3 (4-(2,5-dichloro-3-thienylsulfonylamino)-2- hydroxybenzoic acid), formula 4 (4-[5-chloro-4-(m-isopropoxycarbonylphenyl)-2- thienylsulfonylamino]-2-hydroxybenzoic acid), formula 5 (m-(5-isopropyl-3-methyl-30 1-benzofuran-2-ylsulfonylamino)benzoic acid), formula 6 ((3,5-dimethyl-1- benzothiophen-2-ylsulfonyl)[m-(1H-1,2,3,4-tetrazol-5-yl)phenyl]amine), formula 7 (m-(5-chloro-3-methyl-1-benzothiophen-2-ylsulfonylamino)benzoic acid), formula 8 ((5-Isopropyl-3-methyl-1-benzothiophen-2-ylsulfonyl)[m-(1H-1,2,3,4-tetrazol-5-Docket No. EPN-AC-RAFT.004PC PATENT yl)phenyl]amine), formula 9 (m-(3-biphenylylsulfonylamino)benzoic acid), formula 10 (2-(5-isopropyl-3-methyl-1-benzothiophen-2-ylsulfonylamino)-4-methyl-1,3- thiazole-5-carboxylic acid), formula 11 (4-(5'-fluoro-2'-hydroxy-3- biphenylylsulfonylamino)-2-hydroxybenzoic acid), and salts thereof, the structures of 5 which are shown in FIG 14.

[0116] Embodiment 22. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of the structures of formula 12 (2-Hydroxyethyl 4-(5'-fluoro-2'-hydroxy-3-biphenylylsulfonylamino)-2- hydroxybenzoate), formula 13 ([4-(methylsulfonyl)-3-pyridyl][8-(1-methyl-1H-indol-10 6-yl)-6-quinoxalinyl]amine) formula 14 (N-(tetrahydro-2H-pyran-4-yl)-3-[8-(1- methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 15 ([4- (methylsulfonyl)-3-pyridyl][8-(3-methyl-1-benzothiophen-5-yl)-6- quinoxalinyl]amine), formula 16 (N-[(1-Methyl-3-pyrrolidinyl)methyl]-3-[8-(1- methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 17 (5-(3-[8-15 (1-Methyl-1H-indol-6-yl)-6-quinoxalinylamino]-4-pyridylsulfonylamino)- pyrimidine), formula 18 (N-5-pyrimidinyl-3-[8-(1-methyl-1H-indol-6-yl)-6- quinoxalinylamino]isonicotinamide), formula 19 (N-(1-Methyl-3-piperidyl)-3-[8-(1- methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 20 (N-(1- Methyl-3-pyrrolidinyl)-3-[8-(4-fluoro-1-methyl-1H-indol-6-yl)-6-20 quinoxalinylamino]isonicotinamide), formula 21 ([(S)-(6-Methoxy-3-pyridyl)(3- methyl-3H-1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)-6- quinoxalinyl]amine), formula 22 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3-methyl-3H- 1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)-6-quinoxalinyl]amine), formula 23 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3-methyl-3H-1,2,3-triazol-4- 25 yl)methyl][8-(3-methyl-1-benzofuran-5-yl)-6-quinoxalinyl]amine), and salts thereof, the structures of which are shown in FIG 15.

[0117] Embodiment 23. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of the structures of formula 24 (5-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-bromo-2-phenyl-2H-30 pyridazin-3-one), formula 25 (5-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-iodo-2- phenyl-2H-pyridazin-3-one), formula 26 (5-(4-acetyl-5-methyl-1H-1,2,3-triazol-1- yl)-2-benzyl-4-bromo-2H-pyridazin-3-one), formula 27 (5-(4-Acetyl-5-methyl-1H- 1,2,3-triazol-1-yl)-4-bromo-2-phenethyl-2H-pyridazin-3-one), formula 28 (5-(4-Docket No. EPN-AC-RAFT.004PC PATENT acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-bromo-2-(p-chlorophenyl)-2H-pyridazin-3- one), formula 29 (3-(p-bromophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza-4- indenone), formula 30 (3-(p-chlorophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza- 4-indenone), formula 31 (1-(p-methoxyphenyl)-3-(p-methoxyphenyl)-1,3a,5,6- 5 tetrahydro-1,5,7-triaza-4-indenone), formula 32 (1-(p-bromophenyl)-3-phenyl- 1,3a,5,6-tetrahydro-1,5,7-triaza-4-indenone), formula 33 ({5- azatricyclo[7.4.0.02,6]trideca-1(13),2(6),3,7,9,11-hexaen-4-yl}phenylmethanone), formula 34 ({5-azatricyclo[7.4.0.02,6]trideca-1(13),2(6),3,7,9,11-hexaen-4-yl}(4- pyridyl)methanone hydrochloride), formula 35 ((p-aminophenyl){5- 10 azatricyclo[7.4.0.02,6]trideca-1(13),2(6),3,7,9,11-hexaen-4-yl}methanone), formula 36 ([(S)-1-(m-methoxyphenyl)ethyl][6-(1,3-benzothiazol-6-yl)-2-methyl-4- pyrimidinyl]amine), and salts thereof, the structures of which are displayed in FIG 16.

[0118] Embodiment 24. The method of embodiment 13 or 14 wherein the small 15 molecule PFKFB3 inhibitor is selected from the group consisting of the structures of compound 5 (N-{p-[p-(dimethylamino)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 7 (N-[p-(p-morpholinophenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 8 (N-[p-(p-piperidinophenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 9 (N-{p-[p-(1-pyrrolidinyl)phenoxy]phenyl}-20 (S)-2-pyrrolidinecarboxamide), compound 11 (N-{p-[p- (diethylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 12 (N- {p-[p-(dipropylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 13 (N-{p-[p-(diallylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 14 (N-{p-[p-(1H-imidazol-1-yl)phenoxy]phenyl}-(S)-2-25 pyrrolidinecarboxamide), compound 15 (N-{p-[p-(4-pyridyl)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 16 (N-[p-(4-biphenylyloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 18 (N-{p-[p- (morpholinomethyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 22 (N-[p-(5,6,7,8-tetrahydro-2-naphthyloxy)phenyl]-(S)-2-pyrrolidinecarboxamide),30 compound 27 (N-{p-[p-(trifluoromethyl)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 28 (N-[p-(p-chlorophenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 29 (N-[p-(2-naphthyloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 30 (N-[p-(p-cumenyloxy)phenyl]-(S)-2-Docket No. EPN-AC-RAFT.004PC PATENT pyrrolidinecarboxamide), compound 32 (N-[p-(p-ethoxyphenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 33 (N-[p-(p-methoxyphenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), and salts thereof, the structures of which are shown in FIG 17. 5

[0119] Embodiment 25. The method of embodiment 13 or 14 wherein the small molecule PFKFB3 inhibitor is selected from the group consisting of (E)-3-(p- chlorophenyl)-1-(3-pyridyl)-2-propen-1-one, (E)-3-(1-naphthyl)-1-(4-pyridyl)-2- propen-1-one, N-{p-[(E)-2-isonicotinoyl-1-ethenyl]phenyl}acetamide, (E)-3-(o- chlorophenyl)-1-(2-pyridyl)-2-propen-1-one, (E)-3-(o-chlorophenyl)-1-(3-pyridyl)-2- 10 propen-1-one, and salts thereof.

[0120] Embodiment 26. The method of embodiment 3 wherein the glycolysis inhibitor is a pyruvate kinase inhibitor.

[0121] Embodiment 27. The method of embodiment 26 wherein the pyruvate kinase inhibitor is an antibody or antigen-binding antibody fragment (e.g., a single chain 15 antibody, a single-domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, triabody, tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), a peptibody, a nanobody, a pyruvate kinase binding polypeptide such as 20 TLN232, or a small molecule pyruvate kinase inhibitor.

[0122] Embodiment 28. The method of embodiment 26 or 27 wherein the small molecule pyruvate kinase inhibitor is selected from the group consisting of Shikonin (2-[(S)-1-hydroxy-4-methyl-3-pentenyl]-2,3-dihydro-1,4-naphthalenedione), metformin (3-(azanylazanylidenemethyl)-1,1-dimethylguanidine), VK3 (2-methyl-25 1,4-naphthalenedione), VK5 (4-amino-2-methyl-1-naphthol), Lapachol (3-hydroxy-2- (3-methyl-2-butenyl)-2,3-dihydro-1,4-naphthalenedione), C3k ((3-methyl-1,4-dioxo- 2,3-dihydro-2-naphthyl)methyl 1-piperidinecarbodithioate, benzoxepane ((E)-4-[2-(p- ethylphenyl)ethylidene]-6,8-dimethoxy-2,3-dihydro-1-benzoxepin-5-one), PB2 ((2R,3R,4R,2'R,3'R)-2,2'-bis(3,4-xylyl)-4,8'-bichromane-3,3',5,5',7,7'-hexol),30 Parthenolide (2-[2-(1-{(1S,2R,4R,5S,11S,E)-5-methyl-12-methylene-13-oxo-3,14- dioxatricyclo[9.3.0.02,4]tetradec-7-en-8-yl}ethenyloxy)ethoxy]ethyl (1S,2S,4R,10S,E)-4-methyl-11-methylene-12-oxo-3,13- dioxatricyclo[8.3.0.02,4]tridec-7-ene-8-carboxylate), benserazide (2-amino-3-Docket No. EPN-AC-RAFT.004PC PATENT hydroxy-1-{2-[(2,3,4-trihydroxyphenyl)methyl]hydrazino}-1-propanone, ML-265 (10-[(m-aminophenyl)methyl]-7-methyl-4-(methylsulfinyl)-3-thia-7,10,11- triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,11-tetraen-9-one, and salts thereof, the structures of which are shown in FIG 18. 5

[0123] Embodiment 29. The method of embodiment 26 or 27 wherein the small molecule pyruvate kinase inhibitor is selected from the group consisting of PKL-IN-1 (compound 12a: 2,3,5,6,7-Pentahydroxy-10H-9-oxa-10λ6-thiaphenanthrene-10,10- dione), PKM2-IN-6 (compound 7d: [4-(1,3a-diaza-3-indenyl)-1,3-thiazol-2-yl](o- methoxyphenyl)amine), PKM2-IN-3 ((E)-4-[(p-ethylphenyl)methylene]-6,8-10 dimethoxy-2,3-dihydro-1-benzoxepin-5-one), CIAC001 (2-[(3S,4R)-p-mentha-1,8- dien-3-yl]-5-[1-(2H-1,2,3-triazol-2-yl)ethyl]resorcinol), vitamin K5 (4-amino-2- methyl-1-naphthol), Alkannin (6-[(S)-1-hydroxy-4-methyl-3-pentenyl]-5,8- dihydroxy-1,4-naphthalenedione), PKM2 / PDK1-IN-1 (N-{(R)-2-[(R)-1-(5,8- dihydroxy-1,4-dioxo-2-naphthyl)-4-methyl-3-pentenylthio]-1-methylethyl}5-[(4R)-2-15 (o-tolyl)-1,3-dithian-4-yl]valeramide, PKM2-IN-5 (N-isopropyl-12-methyl-7-oxo-8- oxa-3-thiatricyclo[7.4.0.02,6]trideca-1(13),2(6),4,9,11-pentaene-4-carboxamide, PKM2-IN-4 (Methyl 3-bromo-2-(1-hydroxycyclohexyl)-1-selena-7aλ5-aza-5- indenecarboxylate), and salts thereof, the structures of which are shown in FIG 19.

[0124] Embodiment 30. The method of embodiment 26 or 27 wherein the small 20 molecule pyruvate kinase inhibitor is selected from the group consisting of ellagic acid, silybin and salts thereof.

[0125] Embodiment 31. The method of embodiment 3 wherein the glycolysis inhibitor is a lactate dehydrogenase inhibitor.

[0126] Embodiment 32. The method of embodiment 31 wherein the lactate 25 dehydrogenase inhibitor is an antibody or antigen-binding antibody fragment (e.g., a single chain antibody, a single-domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, triabody, tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense molecule, ribozyme, MiRNA, 30 dsRNA, ssRNA, and shRNA) such as Neodosiran, a peptibody, a nanobody, a lactate dehydrogenase binding polypeptide, or a small molecule lactate dehydrogenase inhibitor.Docket No. EPN-AC-RAFT.004PC PATENT

[0127] Embodiment 33. The method of embodiment 31 or 32 wherein the lactate dehydrogenase inhibitor is selected from the group consisting of Gossypol (1-[8'-acetyl- 1,1',6,6',7'-pentahydroxy-5,5'-bis(isopropyl)-3,3',7-trimethyl-2,2'-binaphthyl-8-yl]-1- ethanone), FX-11 (7-benzyl-2,3-dihydroxy-6-methyl-4-propyl-1-naphthoic acid), 5 Galloflavin (2,5,6,7-tetrahydroxy-4,10-dioxa-3,9-phenanthrenedione), oxamate, Morin (2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxy-4-chromenone), Epigallocatechin gallate ((2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,5,7-chromantriol), GSK2837808A (5-[3- (Cyclopropylaminosulfonyl)-7-(2,4-dimethoxy-5-pyrimidinyl)-4-quinolylamino]-3-(3,5- difluorophenoxy)benzoic acid), GNE-140 (3-(o-Chlorophenylthio)-4-hydroxy-6-(p-10 morpholinophenyl)-6-(3-thienyl)-5,6-dihydro-1H-pyridin-2-one), AXKO-0046 (1-({[3- (2-benzylaminoethyl)-1H-indol-2-yl]methyl}amino)cycloheptane), LDHA-IN-3 (compound 2: trifluoro[p-(phenylseleno)phenyl]methane), NHI-2 (methyl 1-hydroxy-6- phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate), LDHA-IN-4 (AZ33: [(p-{3-[N-2- (N-2-Methyl-1,3-benzothiazol-6-ylcarbamoyl)ethylcarbamoyl]-propyl}phenyl)-15 methyl]malonic acid), LM021 ((E)-3-[p-(dimethylamino)phenyl]-1-(4-hydroxy-3- coumarinyl)-2-propen-1-one), and salts thereof, the structures of which are shown in FIG 20.

[0128] Embodiment 34. The method of embodiment 31 or 32 wherein the lactate dehydrogenase inhibitor is selected from the group consisting of LDH-IN-1 (2-{4-[(p-20 aminosulfophenyl)methyl]-3-(3-biphenylyl)-5-(cyclopropylmethyl)-1H-pyrazol-1-yl}- 1,3-thiazole-4-carboxylic acid), Nifurtimox ((E)-[(5-nitro-2-furyl)methylene](3-methyl- 1,1-dioxo-1λ6,4-thiazinan-4-yl)amine), 3-dehydrotrametenolic acid ((R)-2- {(2S,5S,7R,11R,14S,15R)-5-hydroxy-2,6,6,11,15-pentamethyltetracyclo[8.7.0.02,7.011,15]- heptadeca-1(17),9-dien-14-yl}-6-methyl-5-heptenoic acid), CHK-336 (example 1: 2-{4-25 [(4-aminosulfo-3-fluorophenyl)methyl]-5-(cyclopropylmethyl)-3-(p-fluorophenyl)-1H- pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid), Glomeratose A ((2S,3S,4R,5R)-2- [(2R,3R,4S,5S,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yloxy]-4-hydroxy-2,5- bis(hydroxymethyl)tetrahydro-3-furyl (E)-3-(3,4,5-trimethoxyphenyl)acrylate), anticancer agent 121 (methyl (Z)-3-[3-(p-methoxyphenyl)-4-phenyl-3H-1,3-thiazol-2-30 ylidene]propionate), anticancer agent 122 (methyl (Z)-3-[3-(p-chlorophenyl)-4-phenyl- 3H-1,3-thiazol-2-ylidene]propionate), RS6212 (3-{4-[(6-oxo-4,5-diaza-5- indanyl)methyl]-1-piperidyl}-1H-1λ6,2-benzisothiazole-1,1-dione), antibiofilm agent 5 (ethyl 6-({4-[2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]-1-Docket No. EPN-AC-RAFT.004PC PATENT piperazinyl}methyl)-4-(2-butyl-5-chloro-3H-imidazol-4-yl)-2-oxo-3,4-dihydro-1H- pyrimidine-5-carboxylate), LDHA-IN-6 (compound 6: methyl 3-{N-p-[(1-methyl-1H- imidazol-2-yl)carbonyl]phenylcarbamoyl}-2-[p-(trifluoromethyl)phenyl]propionate), LDHA-IN-7, the corresponding carboxylic acid of LDHA-IN-6 (compound 21: 3-{N-p- 5 [(1-Methyl-1H-imidazol-2-yl)carbonyl]phenylcarbamoyl}-2-[p- (trifluoromethyl)phenyl]propionic acid), NCATS-SM1441 (2-{4-[(4-Aminosulfo-3- fluorophenyl)methyl]-5-(cyclopropylmethyl)-3-{m-[2-(5-methyl-2- thienyl)ethynyl]phenyl}-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid), and salts thereof, the structures of which are shown in FIG 21. 10

[0129] Embodiment 35. The method of embodiment 3 wherein the glycolysis inhibitor is an inhibitor of insulin growth factor receptor type 1 (IGF1R) signaling.

[0130] Embodiment 36. The method of embodiment 35 wherein the IGF1R signaling inhibitor is an antibody such as teprotumumab, MK-0646, MM-141, ganitumab (AMG479), xentuzumab, figitumumab, dalotuzumab, robatumumab (Sch 717454), 15 dusigitumab (MEDI 573), veligrotug, istiratumab, or antigen-binding antibody fragment (e.g., a single chain antibody, a single-domain antibody, a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or another engineered molecule, such as a diabody, triabody, tetrabody, minibody, and a minimal recognition unit), a nucleic acid molecule (e.g., an aptamer, antisense 20 molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA) such as Neodosiran, a peptibody, a nanobody, a lactate dehydrogenase binding polypeptide, or a small molecule IGF1R inhibitor.

[0131] Embodiment 37. The method of embodiment 35 or 36 wherein the IGF1R inhibitor is selected from the group consisting of ceritinib (LDK378: 5-chloro-2-[2-25 isopropoxy-4-(4-piperidyl)-5-toluidino]-4-[o-(isopropylsulfonyl)phenylamino]- pyrimidine), linsitinib (OSI-906): (1s,3s)-3-[7-amino-1-(2-phenyl-7-quinolyl)-2,3a,6- triaza-3-indenyl]-1-methylcyclobutanol), picropodophyllin ((10R,11S,15R,16S)- 11,15,16-trimethyl-10-(3,4,5-trimethoxyphenyl)-4,6,13-trioxatetracyclo- [7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-12-one), PQ401 (3-(5-chloro-2-30 methoxyphenyl)-1-(2-methyl-4-quinolyl)urea), BMS-754807 (N-(6-fluoro-3-pyridyl)-(S)- 1-[7-(5-cyclopropyl-1H-pyrazol-3-ylamino)-3a,4,6-triaza-5-indenyl]-2-methyl-2- pyrrolidinecarboxamide), NVP-AEW541 ((R)-3-{3-[(1-azetidinyl)methyl]-1-azetidinyl}- 1-[m-(benzyloxy)phenyl]-3H-4,6-diazainden-7-ylamine), BMS936524 (3-[(S)-2-(m-Docket No. EPN-AC-RAFT.004PC PATENT chlorophenyl)-2-hydroxyethylamino]-2-(5-morpholino-1H-1,3-benzimidazol-2-yl)-2,4- cyclohexadien-1-one), AZD-3463 (2-[4-(4-amino-1-piperidyl)-2-anisidino]-5-chloro-4- (1H-indol-3-yl)pyrimidine), GSK1838705A (N-methyl-2-(6-{1-[2- (dimethylamino)acetyl]-5-methoxy-6-indolinylamino}-1H-1,5,7-triazainden-4-ylamino)- 5 6-fluorobenzamide), GSK1904529A (N-2,6-difluorophenyl5-{3-[2-(5-ethyl-2-methoxy- 4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidyl}phenylamino)-4-pyrimidinyl]-1,3a- diaza-2-indenyl}-2-anisamide), NBI-31772 (6,7-dihydroxy-4-protocatechuoyl-2- naphthoic acid), and salts thereof, the structures of which are shown in FIG 22.

[0132] Embodiment 38. The method of embodiment 35 or 36 wherein the IGF1R10 inhibitor is selected from the group consisting of NVP-TAE 226 (N-methyl-o-[5-chloro- 2-(2-methoxy-4-morpholinophenylamino)-4-pyrimidinylamino]benzamide), XL228 (4- (5-cyclopropyl-1H-pyrazol-3-ylamino)-2-{[(3-isopropyl-5-isoxazolyl)methyl]amino}-6- (4-methyl-1-piperazinyl)pyrimidine), AG1024 ({[3-bromo-5-(tert-butyl)-4- hydroxyphenyl]methylene}propanedinitrile), chromeceptin (2-amino-7-(dimethylamino)- 15 4-[m-(trifluoromethyl)phenyl]-4H-chromene-3-carbonitrile), Indirubin derivative E804 ((Z)-3-(3,4-dihydroxybutoxyimino)-2,3'-biindolin-2'-one), AZ7550 (N-(2-{N-methyl[2- (methylamino)ethyl]amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)-2- pyrimidinyl]methyl}phenyl)acrylamide), I-OMe tyrphostin AG538 ((E)-[(4-hydroxy-3- iodo-5-methoxyphenyl)methylene]protocatechuoylacetonitrile, IGF1R inhibitor 2 (6-20 fluoro-2-[6-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-7-isoquinolylamino)-1H-1,5,7- triazainden-4-ylamino]benzamide), AG538 ((E)-[(3,4-dihydroxyphenyl)methylene]- protocatechuoylacetonitrile), AZ12253801 ((5-cyclopropyl-1H-pyrazol-3-yl)(2-{(S)-2- methyl-2-[3-(2-pyridyl)-5-isoxazolyl]-1-pyrrolidinyl}-6-methyl-4-pyrimidinyl)amine, and salts thereof, structures of which are shown in FIG 23. 25

[0133] Embodiment 39. The method of embodiment 35 or 36 wherein the IGF1R inhibitor is selected from the group consisting of IGF-1R / SRC-IN-1 (N-(p- tolyl)methyl(1H-indol-3-yl)oxoacetamide), IGF1-R inhibitor 3 (N-{1-[4-(6-cyano-1H- indol-3-yl)butyl]-4-piperidyl}-3-cyano-5-fluoro-1H-indole-7-carboxamide, BMS695735 (4-[2-(4-chloro-1H-pyrazol-1-yl)ethylamino]-3-{5-[1-(3-fluoropropyl)-4-piperidyl]-7-30 methyl-1H-1,3-benzimidazol-2-yl}-1H-pyridin-2-one), chimaphilin (2,7-Dimethyl-1,4- naphthalenedione), SU4343 ((Z)-3-[(p-cumenyl)methylene]-2-indolinone), and salts thereof, the structures of which are shown in FIG 24.Docket No. EPN-AC-RAFT.004PC PATENT

[0134] Embodiment 40. The method of any one of embodiments 1-39 wherein the pharmaceutically acceptable formulation is administered by the intranasal, intrathecal, oral, or parenteral routes.

[0135] Embodiment 41. The method of embodiment 40 wherein the pharmaceutically 5 acceptable formulation is administered by the intrathecal route.

[0136] Embodiment 42. The method of embodiment 40 wherein the pharmaceutically acceptable formulation is administered by the intravenous route.

[0137] Embodiment 43. The method of embodiment 40 wherein the pharmaceutically acceptable formulation is administered by the subcutaneous route. 10

[0138] Embodiment 44. The method of embodiment 40 wherein the pharmaceutically acceptable formulation is administered by the intranasal route.

[0139] Embodiment 45. The method of embodiment 40 wherein the pharmaceutically acceptable formulation is administered by the oral route.

[0140] Embodiment 46. The method of any one of embodiments 1-45 wherein the 15 pharmaceutically acceptable formulation is administered for the treatment of neuropathic pain.

[0141] Embodiment 47. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain. 20

[0142] Embodiment 48. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a TLR4- mediated allodynia, post nerve or tissue injury pain or neuropathic pain.

[0143] Embodiment 49. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a TLR4- 25 mediated allodynia, post nerve or tissue injury pain or neuropathic pain.

[0144] Embodiment 50. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a tissue injury pain or neuropathic pain generated or caused by, or is a sequela to, trauma.

[0145] Embodiment 51. The method of any one of embodiments 1-45 wherein the30 pharmaceutically acceptable formulation is administered for the treatment of a post- surgical pain or neuropathic pain.Docket No. EPN-AC-RAFT.004PC PATENT

[0146] Embodiment 52. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the prevention of a post- surgical pain or neuropathic pain.

[0147] Embodiment 53. The method of embodiment 51 or 52 wherein the 5 pharmaceutically acceptable formulation is administered by the parenteral or oral routes.

[0148] Embodiment 54. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a chemotherapy-induced pain or neuropathic pain.

[0149] Embodiment 55. The method of any one of embodiments 1-45 wherein the 10 pharmaceutically acceptable formulation is administered for the prevention of a chemotherapy-induced pain or neuropathic pain.

[0150] Embodiment 56. The method of embodiment 54 or 55 wherein the pharmaceutically acceptable formulation is administered by the intrathecal, parenteral or oral routes. 15

[0151] Embodiment 57. The method of any one of embodiments 1-45 wherein the pharmaceutically acceptable formulation is administered for the treatment of a primary headache, a migraine or a cluster headache.

[0152] Embodiment 58. The method of embodiment 57 wherein the pharmaceutically acceptable formulation is administered by the intranasal, parenteral or oral routes. 20

[0153] Embodiment 59. Use of a pharmaceutically acceptable formulation in the manufacture of a medicament wherein the pharmaceutically acceptable formulation is comprised of at least one glycolysis inhibitor of any one of embodiments 1-39 and one or more pharmaceutically acceptable excipients.

[0154] Products of Manufacture, Kits 25

[0155] Also provided are products of manufacture such as implants or pumps, kits and pharmaceuticals for practicing the methods as provided herein. In alternative embodiments, provided are products of manufacture, kits and / or pharmaceuticals comprising all the components needed to practice a method as provided herein. In alternative embodiments, kits also comprise instructions for practicing a method as 30 provided herein.

[0156] Formulations and pharmaceutical compositions

[0157] In alternative embodiments, provided are pharmaceutical formulations or compositions for use in in vivo, in vitro or ex vivo methods to treat, prevent, reverseDocket No. EPN-AC-RAFT.004PC PATENT and / or ameliorate neuropathic pain. In alternative embodiments, pharmaceutical compositions and formulations used to practice methods and uses as provided herein comprise glycolysis inhibitors that are administered to an individual in need thereof in an amount sufficient to treat, prevent, reverse and / or ameliorate, for example, post-operative 5 pain, a neuropathic pain or a headache such as migraine.

[0158] In alternative embodiments, the pharmaceutical compositions used to practice methods and uses as provided herein are administered parenterally. The pharmaceutical compositions are formulated in any way and administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general 10 medical condition of each patient, the resulting preferred method of administration and the like. Details on techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co., Easton PA (“Remington’s”).

[0159] For example, in alternative embodiments, the compositions used to practice 15 methods and uses as provided herein are formulated in a buffer, in a saline solution, in a vesicle, in a liposome, in a nanoparticle, in a nanolipoparticle and the like. In alternative embodiments, the compositions are formulated and applied in a variety of concentrations and forms depending on the desired in vivo, in vitro or ex vivo conditions, a desired in vivo, in vitro or ex vivo method of administration and the like. Details on techniques for 20 in vivo, in vitro or ex vivo formulations and administrations are well described in the scientific and patent literature.

[0160] In alternative embodiments, formulations and pharmaceutical compositions used to practice methods and uses as provided herein typically comprise a solution of compositions (which include peptidomimetics, racemic mixtures or racemates, isomers, 25 stereoisomers, derivatives and / or analogs of compounds) disposed in or dissolved in a pharmaceutically acceptable carrier, for example, acceptable vehicles and solvents that are typically employed include water and Ringer's solution, an isotonic sodium chloride.

[0161] In one embodiment, solutions and formulations used to practice methods and uses as provided herein are sterile and are manufactured to be generally free of 30 undesirable matter.

[0162] In one embodiment, these solutions and formulations are sterilized by conventional, well known sterilization techniques.Docket No. EPN-AC-RAFT.004PC PATENT

[0163] In some embodiments, the solutions and formulations used to practice methods and uses as provided herein auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium 5 chloride, sodium lactate and the like. The concentration of active agent in these formulations vary, and are selected primarily based on fluid volumes, viscosities and the like, in accordance with the particular mode of in vivo, in vitro or ex vivo administration selected and the desired results.

[0164] The compositions and formulations used to practice methods and uses as 10 provided herein in some embodiments are delivered by the use of liposomes. By using liposomes, particularly where the liposome surface carries ligands specific for target cells (for example, an injured or diseased neuronal cell or CNS tissue), or are otherwise preferentially directed to a specific tissue or organ type, one will typically focus the delivery of the active agent into a target cell in an in vivo, in vitro or ex vivo application. 15

[0165] Nanoparticles, Nanolipoparticles and Liposomes

[0166] Also provided are nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds used to practice methods and uses as provided herein, for example, to deliver compositions comprising recombinant glycolysis inhibitor polypeptides in vivo, for example, to the CNS and brain. 20

[0167] In alternative embodiments, these compositions are designed to target specific molecules, including biologic molecules, such as polypeptides, including cell surface polypeptides, for example, for targeting a desired cell type or organ, for example, a nerve cell or the CNS, and the like.

[0168] Provided are multilayered liposomes comprising compounds used to practice 25 methods and uses as provided herein, for example, as described in Park, et al., U.S. Pat. Pub. No.20070082042.

[0169] The multilayered liposomes are sometimes prepared using a mixture of oil- phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition used 30 to practice methods and uses as provided herein.

[0170] Liposomes are typically made using a method as described in Park, et al., U.S. Pat. Pub. No.20070042031, including method of producing a liposome by encapsulating an active agent (for example, glycolysis inhibitor nucleic acids and polypeptides), theDocket No. EPN-AC-RAFT.004PC PATENT method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution with the organic lipid solution in a first mixing region to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously 5 produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution.

[0171] In one embodiment, liposome compositions used to practice methods and uses as provided herein comprise a substituted ammonium and / or polyanions, for example, for targeting delivery of a compound (for example, a glycolysis inhibitor polypeptide) to a 10 desired cell type (for example, an endothelial cell, a nerve cell, or any tissue or area, for example, a CNS, in need thereof), as described for example, in U.S. Pat. Pub. No. 20070110798.

[0172] Provided are nanoparticles comprising compounds (for example, glycolysis inhibitors used to practice methods provided herein) in the form of active agent- 15 containing nanoparticles (for example, a secondary nanoparticle), as described, for example, in U.S. Pat. Pub. No.20070077286. In one embodiment, provided are nanoparticles comprising a fat-soluble active agent or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt.

[0173] In one embodiment, solid lipid suspensions are used to formulate and to 20 deliver compositions used to practice methods and uses as provided herein to mammalian cells in vivo, for example, to the CNS, as described, for example, in U.S. Pat. Pub. No. 20050136121.

[0174] Delivery vehicle modifications

[0175] In alternative embodiments, glycolysis inhibitor peptides or polypeptides, or 25 glycolysis inhibitor-comprising nanoparticles, liposomes and the like (for example, comprising or having contained therein recombinant glycolysis inhibitor polypeptides used to practice methods provided herein) are modified to facilitate intrathecal injection, for example, delivery into the cerebrospinal fluid or brain. For example, in alternative embodiments, glycolysis inhibitor-comprising nanoparticles, liposomes and the like, are 30 engineered to comprise a moiety that allows the glycolysis inhibitor peptides or polypeptides, or glycolysis inhibitor-comprising nanoparticles, liposomes and the like, to bind to a receptor or cell membrane structure that facilitates delivery into the CNS or brain, for example, where the moiety in some embodiments comprises a mannose-6-Docket No. EPN-AC-RAFT.004PC PATENT phosphate receptor, a melanotransferrin receptor, a LRP receptor or any other receptor that is ubiquitously expressed on the surface of any CNS or brain cell. For example, conjugation of mannose-6-phosphate moieties allows the glycolysis inhibitor peptides or polypeptides, or glycolysis inhibitor-comprising nanoparticles, liposomes and the like, to 5 be taken up by a CNS cell that expresses a mannose-6-phosphate receptor.

[0176] In alternative embodiments, any protocol or modification of the glycolysis inhibitor peptides or polypeptides, or glycolysis inhibitor-comprising nanoparticles, liposomes and the like, that facilitates entry or delivery into the CNS or brain in vivo are used, for example, as described in USPN 9,089,566. 10

[0177] In alternative embodiments, recombinant glycolysis inhibitor peptides or polypeptides, or glycolysis inhibitor-comprising nanoparticles, liposomes and the like (for example, comprising or having contained therein glycolysis inhibitor nucleic acids or polypeptides used to practice methods provided herein) are directly or indirectly linked or conjugated to any blood brain barrier (BBB)-targeting agent, for example, a transferrin,15 an insulin, a leptin, an insulin-like growth factor, a cationic peptide, a lectin, a Receptor- Associated Protein (RAP) (a 39 kD chaperone localized to the endoplasmic reticulum and Golgi, a lipoprotein receptor-related protein (LRP) receptor family ligand), an apolipoprotein B-100 derived peptide, an antibody (for example, a peptidomimetic monoclonal antibody) to a transferrin receptor, an antibody (for example, a 20 peptidomimetic monoclonal antibody) to the insulin receptor, an antibody (for example, a peptidomimetic monoclonal antibody) to the insulin-like growth factor receptor, an antibody (for example, a peptidomimetic monoclonal antibody) to the leptin receptor and the like. In alternative embodiments, protocols for modifications of glycolysis inhibitor peptides or polypeptides, or glycolysis inhibitor-comprising nanoparticles, liposomes and 25 the like, that facilitates crossing of the BBB are used, for example, as described in US Pat App Pub Nos.20050142141; 20050042227. For example, to enhance CNS or brain delivery of a composition used to practice methods as provided herein, various protocols are available, for example: modification of glycolysis inhibitor -comprising nanoparticles, liposomes as described herein and the like to alter tissue distribution. 30

[0178] Delivery vehicles

[0179] In alternative embodiments, a delivery vehicle is used to practice the methods or uses as provided herein, for example, to deliver compositions (for example, recombinant glycolysis inhibitor polypeptides) to a CNS or a brain in vivo. For example,Docket No. EPN-AC-RAFT.004PC PATENT delivery vehicles comprising polycations, cationic polymers and / or cationic peptides, such as polyethyleneimine derivatives, are used for example as described, for example, in U.S. Pat. Pub. No. 20060083737.

[0180] In one embodiment, a dried polypeptide-surfactant complex is used to 5 formulate a composition used to practice methods as provided herein, for example as described, for example, in U.S. Pat. Pub. No.20040151766.

[0181] In one embodiment, a composition used to practice methods and uses as provided herein are applied to cells using vehicles with cell membrane-permeant peptide conjugates, for example, as described in U.S. Patent Nos.7,306,783; 6,589,503. In one 10 aspect, the composition to be delivered is conjugated to a cell membrane-permeant peptide. In one embodiment, the composition to be delivered and / or the delivery vehicle are conjugated to a transport-mediating peptide, for example, as described in U.S. Patent No.5,846,743, describing transport-mediating peptides that are highly basic and bind to poly-phosphoinositides. 15

[0182] Dosage and Administration Thereof

[0183] The pharmaceutical compositions and formulations used to practice methods and uses as provided herein are administered for prophylactic and / or therapeutic treatments. In therapeutic applications, compositions are administered to a subject already suffering from a disease, condition, infection or defect in an amount sufficient to 20 cure, alleviate or partially arrest the clinical manifestations of the disease, condition, infection or disease and its complications (a “therapeutically effective amount”), including for example, a neuropathic pain. For example, in alternative embodiments, glycolysis inhibitor-comprising pharmaceutical compositions and formulations as provided herein are administered to an individual in need thereof in an amount sufficient 25 to treat, prevent, reverse and / or ameliorate a neuropathic pain, an inflammation-induced neuropathic pain, an inflammation-induced neuropathic pain, a nerve or CNS inflammation, a allodynia, a post nerve injury pain or neuropathic pain, a post-surgical pain or neuropathic pain, a migraine, or a hyperalgesia.

[0184] The amount of pharmaceutical composition adequate to accomplish this is 30 defined as a "therapeutically effective dose." The dosage schedule and amounts effective for this use, i.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient’s physical status, age and the like. In calculatingDocket No. EPN-AC-RAFT.004PC PATENT the dosage regimen for a patient, the mode of parenteral administration also is taken into consideration.

[0185] In alternative embodiments these dosages are administered once a day, once a week, or any variation thereof as needed to maintain therapeutic levels of glycolysis 5 inhibitor, which are monitored by measuring actually glycolysis inhibitor levels or by monitoring of therapeutic effect, for example, diminishing of pain. The dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents’ rate of absorption, bioavailability, metabolism, clearance, and the like (see, for example, Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol.58:611-617; 10 Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci.84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol.24:103-108; the latest Remington’s, supra). The state of the art allows the clinician to determine the dosage regimen for each individual patient, active agent and disease or condition treated. Guidelines provided for similar 15 compositions used as pharmaceuticals are typically used as guidance to determine the dosage regiment, i.e., dose schedule and dosage levels, administered practicing the methods as provided herein are correct and appropriate.

[0186] Single or multiple administrations of formulations are given depending on the dosage and frequency as required and tolerated by the patient. The formulations should 20 provide a sufficient quantity of active agent to effectively treat, prevent or ameliorate a conditions, diseases or symptoms as described herein. For example, alternative exemplary pharmaceutical formulations for parenteral administration of compositions used to practice methods as provided herein are in a daily amount of between about 0.1 to 0.5 to about 20, 50, 100 or 1000 or more ug per kilogram of body weight per day. In an 25 alternative embodiment, dosages are from about 0.3 mg to about 30 mg per kg of body weight per patient per day are used. Lower dosages are sometimes administered into the blood stream, into a body cavity or into a lumen of an organ. Typical methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's, 30 supra.

[0187] Kits and Instructions

[0188] Provided are kits comprising compositions (including the devices as described herein) and / or instructions for practicing methods as provided herein to for example, treat,Docket No. EPN-AC-RAFT.004PC PATENT ameliorate or prevent a neuropathic pain. In alternative embodiments, provided are kits comprising: a composition used to practice a method as provided herein, or a composition, a pharmaceutical composition or a formulation as provided herein, and in some embodiments comprising instructions for use thereof. 5

[0189] The invention will be further described with reference to the examples described herein; however, it is to be understood that the invention is not limited to such examples. EXAMPLES

[0190] Example 1: Efficacy of 3PO and IGF1R neutralizing antibody in reducing 10 allodynia in a mouse model of chemotherapy induced peripheral neuropathy (CIPN)

[0191] Example 1 describes studies using a mouse model of CIPN, where spinal microglia are characterized by the presence of inflammarafts - enlarged, cholesterol- enriched lipid rafts, which organize the inflammatory response. Manipulation of specific mechanisms that regulate cholesterol metabolism and normalize inflammarafts and 15 reprogram microglia, results in a long-lasting alleviation of neuropathic pain.

[0192] WT male C57BL / 6 mice were purchased from Jackson Laboratories. Cisplatin was purchased from Spectrum Chemical and diluted in PBS, according to the manufacturer. To develop CIPN, i.p. injections of cisplatin (2.3 mg / kg / injection; Spectrum Chemical MFG) were performed on day 1 and day 3. During the period of 20 cisplatin administration, weight loss, behavioral changes, and mechanical allodynia were monitored and measured. The criteria for euthanasia were weight loss in excess of 20% body weight and erratic behavior; however, no animals required euthanasia.

[0193] Intrathecal injections. Intrathecal injections were performed on cisplatin-treated mice. Briefly, mice were anesthetized using 5% isoflurane in oxygen for induction and 25 2% isoflurane in oxygen for maintenance of anesthesia. The lower back of the animals was shaved and disinfected, then placed in a prone posture holding the pelvis between the thumb and forefinger. The L5 and L6 vertebrae were identified by touch, and a 30G needle was inserted percutaneously on the midline between the L5 and L6 vertebrae. Successful entry was assessed by the observation of a tail flick. Injections of 5 μl were 30 administered over an interval of ∼30 s. Drugs for i.t. delivery were prepared or diluted in sterile 0.9% NaCl. Following recovery from anesthesia, mice were evaluated for normal motor coordination and muscle tone.Docket No. EPN-AC-RAFT.004PC PATENT

[0194] Mechanical allodynia measurements. Animals were placed in clear, plastic, bottomless cages over a wire mesh surface and acclimated to the set up for 2 hours, 1 day prior to initiation of the experiment. On experimental days, mice were acclimated at least 30 min before the initiation of testing. Tactile thresholds were measured with a series of 5 von Frey filaments (Bioseb) ranging from 2.44 to 4.31 (0.02–2.00 g). The withdrawal response to each filament was recorded and the 50% probability of withdrawal threshold was calculated. Mechanical withdrawal thresholds were assessed before treatment (baseline or day 0) and at days 4, 7, 8, 9,10, 14, 17, and 21 after initiation of the model using the up-down method (Chaplan, 1994). 10

[0195] Assessment of drug treatment on allodynia in CIPN mice. Mice were treated with cisplatin as described and tested for reductions in mechanical thresholds. Allodynic mice were assigned to test groups and a group of naïve mice (did not receive cisplatin) retained for reference. At day 7, groups of mice received either vehicle (saline), 3PO (FIG 6A: dissolved in 10% DMSO in saline; Sigma Aldrich, cat #525330) or IGF1R neutralizing 15 antibody (R&D Systems cat#MAB391). A further control group of cisplatin-treated mice received an injection of IgG antibody (Novus Biologicals-Biotechne, cat # AB-108-C). Allodynia was further assessed at days 8, 9,10, 14, 17, and 21 to assess drug effects. FIG. 2 illustrates the alleviation of pain by inhibitors of cellular glycolysis in a mouse model of chemotherapy induced peripheral neuropathy (CIPN). Wild type mice received 20 intraperitoneal (i.p.) saline (naive group) or cisplatin (two injections of 2.3 mg / kg / day: CIPN). CIPN groups received intrathecal (i.t.) injection of 3PO (1.75 µg / 5µL: CIPN+3PO), or a neutralizing anti-IGF1R antibody (0.25 µg / 5µL: CIPN+IGF1RAb), IgG control (0.25 µg / 5µL) or vehicle (12.6% PBS in saline) were included. Following a single administration of either inhibitor, reversal of tactile thresholds was observed over a period 25 of 14 days post treatment. Mean ± SEM; *, p < 0.05; **, p < 0.01 ***, p < 0.001, tested by Two-way ANOVA with Tukey’s test for multiple comparisons in grouped analyses.

[0196] Example 2: Measurement of effects of drug treatment on TLR4 proximity to lipid rafts, TLR4 dimers and lipid raft content in spinal microglia.

[0197] From the drug treated mice in Example 1, analysis of lipid rafts was performed on 30 isolated cell suspensions.

[0198] Single cell suspension and flow cytometry analysis of inflammarafts. Lumbar spinal cords were harvested by hydraulic extrusion (Richner, 2017), and single-cell suspensions from lumbar tissue were obtained using a Neural Tissue Dissociation kitDocket No. EPN-AC-RAFT.004PC PATENT (Miltenyi Biotec) according to the manufacturer’s protocol. Briefly, tissues were cut into smaller pieces and enzymatically digested. After digestion, suspensions were mixed with debris removal solution (Miltenyi Biotec) and centrifuged according to manufacturer instructions. After debris removal, Myelin Removal Beads II (Miltenyi Biotec) were 5 added to samples and incubated for 15 min at 4°C, followed by separation with LS column and a MACS Separator (Miltenyi Biotec), to remove myelin. Following isolation, cells were incubated with a 1:1000 dilution of Life / Death Ghost Red 780 dye (Cell Signaling) for 30 min on ice. After live / dead cell staining, cells were fixed with 4% formaldehyde for 10 min on ice, washed and incubated with 2% normal mouse serum 10 containing an anti–CD16 / CD32 antibody (BD Bioscience; FcγR blocker) for 30 min on ice, followed by staining with an antibody mix of 1:100 PerCP-Cy5.5–conjugated CD11b antibody (BioLegend; RRID:AB_893232), 1:100 PeCy7- conjugated anti-TMEM119 antibody (eBioscience; Catalog # 25-6119-82), PE-conjugated TLR4 / MD2 (clone MTS510), APC-conjugated TLR4 (clone SA15-21) antibodies (ThermoFisher Scientific; 15 RRID:AB_2562503 and BioLegend; RRID:AB_466263, respectively), and 1:200 dilution of CTB-Alexa594 for lipid rafts (ThermoFisher Scientific) for 45 min on ice. Cells were washed and analyzed using a CytoFLEX flow cytometer (Beckman Coulter).

[0199] For staining compensations, beads were used to compensate the signal overlap between channels and fluorescence minus one control were used to delineate gates. Data 20 were analyzed by FlowJo (BD Bioscience; RRID:SCR_008520).

[0200] The TLR4 dimerization analysis uses two TLR4 antibodies; MTS510 recognizes TLR4 / MD2 as a monomer (in TLR4 units) but not a dimer; SA15-21 binds to any cell surface TLR4 irrespective of its dimerization status [Akashi (2003), Zanoni (2016)]. From these flow cytometry data, the percentage of TLR4 dimers was calculated from the 25 ratio of MTS510 and SA15-21 measured in the same cell suspension. A relative change in the number of TLR4 dimers in spinal microglia was calculated (zero dimers were arbitrarily assigned to unstimulated or naive cells), the abundance of lipid rafts by the geometric mean of each channel fluorescence intensity.

[0201] Proximity ligation assay (PLA). TLR4 localization to lipid rafts, (TLR4-CTB) 30 assemblies were assessed using NaveniFlex PLA reagents (Navinci NaveniFlex GM) according to manufacturer's instructions. Briefly, after fixation, spinal cell suspensions were incubated with Navenci blocking solution at 37°C for 60 min each in a round- bottom well 96 well plate at room temperature. For lipid raft (GM1 ganglioside) binding,Docket No. EPN-AC-RAFT.004PC PATENT an unconjugated CTB (Sigma Aldrich C9903) was incubated at room temperature for 60 min and washed three times with TBS, and then cells were incubated with an anti-TLR4 (Abcam ab22048) and anti-CTB (Sigma 227040) antibodies at room temperature for 1 hour. The samples were incubated with a mixture of Navenibody 1 and 2 at 37°C for 60 5 min in the 96 well plate inside a humidified chamber, enzyme A in reaction buffer A for 60 min, enzyme B in reaction buffer B for amplification overnight at room temperature, and finally, enzyme C in reaction buffer C (Texas red) for 90 min at 37°C.

[0202] FIG.3 illustrates the disruption of lipid “inflammarafts” on spinal microglia of cellular glycolysis inhibitors in the same CIPN animal model (FIG.2).3PO affords 10 statistically significant changes in TLR4 associated with spinal microglia (A), normalization of TLR4 dimers relative to control (B) and a trend to lipid raft reduction (C). IGF1R antibody showed a trend to reduction in these parameters. Flow cytometry analysis of CD11b+ / TMEM119+ spinal microglia cells showing A: TLR4 proximity to lipid rafts (CTB) by PLA signal. B: TLR4 dimers, and C: lipid raft content measured by 15 CTB staining, in spinal microglia from same animals terminated on day 21. Mean ± SEM; *, p < 0.05; **, p < 0.01 ***, p < 0.001, tested by One-way ANOVA with Tukey’s test for multiple comparisons in grouped analyses. CITATIONS

[0203] 1. Brattwall M, Warrén Stomberg M, Rawal N, Segerdahl M, Jakobsson J, Houltz 20 E. Patients' assessment of 4-week recovery after ambulatory surgery. Acta Anaesthesiol Scand.2011; 55:92-98.

[0204] 2. Tran TT, Kaneva P, Mayo NE, Fried GM, Feldman LS. Short-stay surgery: what really happens after discharge? Surgery.2014; 156:20-27.

[0205] 3. Krakowski JC, Hallman MJ, Smeltz AM. Persistent Pain After Cardiac Surgery: 25 Prevention and Management. Semin Cardiothorac Vasc Anesth. 2021:10892532211041320.

[0206] 4. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, Steiner T, Zwart J-A. The Global Burden of Headache: A Documentation of Headache Prevalence and Disability Worldwide. Cephalalgia.2007;27:193-210. 30

[0207] 5. Vetvik KG, MacGregor EA. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol.2017;16:76-87.Docket No. EPN-AC-RAFT.004PC PATENT

[0208] 6. Miller, Y.I., Navia-Pelaez, J.M., Corr, M., and Yaksh, T.L. (2020). Lipid rafts in glial cells: role in neuroinflammation and pain processing. J Lipid Res 61, 655-666..

[0209] 7. Karasinska JM, de Haan W, Franciosi S, Ruddle P, Fan J, Kruit JK, Stukas S, Lütjohann D, Gutmann DH, Wellington CL, Hayden MR. (2013). ABCA1 influences 5 neuroinflammation and neuronal death. Neurobiol Dis.54: 445-55.

[0210] 8. Tall AR, Yvan-Charvet L. (2015). Cholesterol, inflammation and innate immunity. Nat Rev Immunol.15(2):104-16.

[0211] 9. Yvan-Charvet, L., Welch, C., Pagler, T.A., Ranalletta, M., Lamkanfi, M., Han, S., Ishibashi, M., Li, R., Wang, N., and Tall, A.R. (2008). Increased inflammatory gene 10 expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 118, 1837-1847.

[0212] 10. Hidalgo-Aragones MI, Purohit A, Parish D, Sahm UG, Pouton CW, Potter BV, Reed MJ. (1996). Pharmacokinetics of oestrone-3-O-sulphamate. J Steroid Biochem Mol 15 Biol.58(5-6):611-7.

[0213] 11. Groning R, Braun FJ. (1996). Three-dimensional solubility parameters and their use in characterising the permeation of drugs through the skin. Pharmazie. 51(5):337-41.

[0214] 12. Fotherby K. (1996). Bioavailability of orally administered sex steroids used in 20 oral contraception and hormone replacement therapy. Contraception 54:59-69.

[0215] 13. Johnson ME, Blankschtein Langer DR. (1995). Permeation of steroids through human skin. J. Pharm. Sci.84:1144-1146.

[0216] 14. Rohatagi S, Hochhaus G, Möllmann H, Barth J, Derendorf H. (1995). Pharmacokinetic interaction between endogenous cortisol and exogenous corticosteroids. 25 Pharmazie 50:610-613.

[0217] 15. Brophy TR, McCafferty J, Tyrer JH, Eadie MJ. (1983). Bioavailability of oral dexamethasone during high dose steroid therapy in neurological patients. Eur. J. Clin. Pharmacol.24:103-108.

[0218] 16. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. (1994). Quantitative 30 assessment of tactile allodynia in the rat paw. Journal of Neuroscience Methods. Volume 53, Issue 1. Pages 55-63.

[0219] 17. Richner M, Jager SB, Siupka P, Vaegter CB. (2017). Hydraulic Extrusion of the Spinal Cord and Isolation of Dorsal Root Ganglia in Rodents. J Vis Exp. (119):55226.Docket No. EPN-AC-RAFT.004PC PATENT

[0220] 18. Akashi S, Saitoh S-I, Wakabayashi Y, Kikuchi T, Takamura N, Nagai Y, Kusumoto Y, Fukase K, Kusumoto S, Adachi Y, Kosugi A, Miyake K. (2003). Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14. J Exp Med 198, 1035-1042. 5

[0221] 19. Zanoni I, Tan Y, Di Gioia M, Broggi A, Ruan J, Shi J, Donado CA, Shao F, Wu H, Springstead JR, Kagan JC. (2016). An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232-1236.

Claims

Docket No. EPN-AC-RAFT.004PC PATENT WHAT IS CLAIMED IS:

1.

1. A method of treatment or prevention of pain with an inhibitor of cellular glycolysis wherein the pain is neuropathic pain, inflammation-induced 5 neuropathic pain, a Toll-like receptor 4 (TLR4)-mediated inflammation-induced neuropathic pain, nerve or CNS inflammation, a TLR4-mediated nerve or CNS inflammation, allodynia, a TLR4-mediated allodynia, a post nerve or tissue injury pain or neuropathic pain, a post nerve or tissue injury pain or neuropathic pain generated or caused by, or is a sequela to, trauma, a post-surgical pain or 10 neuropathic pain, chemotherapy-induced neuropathic pain, a primary headache, wherein is some aspects is a migraine or a cluster headache, and hyperalgesia, wherein the cellular glycolysis inhibitor comprises a therapeutically effective amount of said glycolysis inhibitor administered in a pharmaceutically acceptable formulation, wherein administration is either by the intranasal, intrathecal, oral, or 15 parenteral routes.

2. The method of claim 1 wherein the glycolysis inhibitor is an inhibitor of any one of the components of the cellular glycolysis pathway or a protein shown to regulate the cellular glycolysis pathway. 20 3. The method of claim 2 wherein the glycolysis inhibitor is an inhibitor of the glucose transporter 1 (GLUT 1), Hexokinase, 6-phosphofructo-2-kinase / fructose- 2,6-biphosphatase 3 (PFKFB3), pyruvate dehydrogenase kinase (PDHK), lactate dehydrogenase, or an inhibitor of Insulin-like growth factor 1 receptor (IGF1R) 25 signaling.

4. The method of claim 3 wherein the glycolysis inhibitor is an inhibitor of PFKFB3.

5. The method of claim 3 wherein the glycolysis inhibitor is an inhibitor of IGF1R 30 signaling.

6. The method of claim 3 wherein the glycolysis inhibitor is an antibody or antigen-binding antibody fragment, typically a single chain antibody, a single-Docket No. EPN-AC-RAFT.004PC PATENT domain antibody, a Fab fragment, F(ab')2fragment, Fd fragment, Fv fragment, scFv, dAb fragment, or other engineered antigen-binding antibody fragment, typically a diabody, triabody, tetrabody, minibody, or a minimal antigen recognition unit, or wherein the glycolysis inhibitor is a nucleic acid molecule, 5 typically an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), a peptibody, a nanobody, or wherein the glycolysis inhibitor is an inhibitory binding polypeptide, peptoid, or a small molecule glycolysis inhibitor of any one of claim 3. 10 7. The method of any one of claims 1-6 wherein the glycolysis inhibitor is an antibody, a single chain antibody, a single-domain antibody, or an antigen- binding antibody fragment, typically a Fab fragment, F(ab')2 fragment, Fd fragment; Fv fragment, scFv, dAb fragment, or other engineered antigen- binding molecule, typically a diabody, triabody, tetrabody, minibody, or a 15 minimal antigen recognition unit, or wherein the glycolysis inhibitor is a nucleic acid molecule, typically an aptamer, antisense molecule, ribozyme, MiRNA, dsRNA, ssRNA, and shRNA), or wherein the glycolysis inhibitor is a peptibody, a nanobody, an inhibitory binding polypeptide, peptoid, or is a small molecule selected from the group consisting of ritonavir, hexokinase II20 VDAC binding domain peptide, P1 ((S)-2-[(S)-2-[(S)-2-{(S)-2-[(S)-2-Amino-3- hydroxypropionylamino]-3-phenylpropionylamino}-4-methylvalerylamino]-4- methylvalerylamino]-6-amidinohexanamide), P2 ((R)-2-({[(R)-2-Amino-3- (1H-indol-3-yl)propionylamino]methyl}carbonylamino)-3-(p- hydroxyphenyl)propionic acid), P3 ((2S,3R)-2-[(S)-2-[(S)-2-[({(S)-2-[(S)-2-25 Amino-3-(p-hydroxyphenyl)propionylamino]-3- hydroxypropionylamino}methyl)carbonylamino]-3-phenylpropionylamino]-4- methylvalerylamino]-3-hydroxybutyric acid), TLN232, teprotumumab, MK- 0646, MM-141, ganitumab (AMG479), xentuzumab, figitumumab, dalotuzumab, robatumumab (Sch 717454), dusigitumab (MEDI 573), 30 veligrotug, istiratumab, and salts thereof.

8. The method of any one of claims 1-6 wherein the glycolysis inhibitor is a small molecule selected from the group consisting of Cytochalesin B, Phloretin (3-(p-Docket No. EPN-AC-RAFT.004PC PATENT hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-1-propanone), Quercetin (2-(3,4- dihydroxyphenyl)-3,5,7-trihydroxy-4-chromenone), Genistein (5,7-dihydroxy-3- (p-hydroxyphenyl)-4-chromenone), Apigenin (5,7-dihydroxy-2-(p- hydroxyphenyl)-4-chromenone), Silibenin ( 2-[(2R,3R)-3-(4-hydroxy-3- 5 methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-3,5,7- trihydroxy-4-chromenone), PUG-1 (8-[(S)-1-hydroxyethyl]-1,7-dihydro-6- purinone), Chromopynone 1 (N-[2-(p-tolyl)ethyl]m-{(1R,9R)-6-ethoxy-9-methyl- 11-oxo-8-oxa-10,12-diazatricyclo[7.3.1.02,7]trideca-2,4,6-trien-10- yl}benzamide), Fasentin (N-[4-chloro-3-(trifluoromethyl)phenyl]acetoacetamide),10 Trehalose ( (2R,3R,4S,5S,6R)-2-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol), WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy)phenyl m- hydroxybenzoate), STF31 (N-3-pyridylp-[p-(tert- butyl)phenylsulfonylamino]benzamide, Curcumin ((1E,6E)-1,7-bis(4-hydroxy-3-15 methoxyphenyl)-1,6-heptadiene-3,5-dione), BAY-876 (N-{1-[(p- cyanophenyl)methyl]-5-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl}-2- [(aminooxy)methyl]-7-fluoro-4-quinolinecarboxamide, 2-deoxy-d-glucose (2- DG), 3-bromopyruvate (3-BrPA), metformin (3-(Azanylazanylidenemethyl)-1,1- dimethylguanidine), hexokinase 2 inhibitor 1 ([(E)-3-(2,3,4-trihydroxyphenyl)-2-20 triazen-1-yl](p-nitrophenyl)methanone, lonidamine (1-[(2,4- dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid), metrizamide (N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]- 1,3-bis(N-methylacetylamino)-2,4,6-triiodo-5-benzamide, benitrobenrazide ({(E)- 2-[(2,3,4-trihydroxyphenyl)methylene]hydrazino}(p-nitrophenyl)methanone,25 benserazide (2-amino-3-hydroxy-1-{2-[(2,3,4- trihydroxyphenyl)methyl]hydrazino}-1-propanone), Oroxylin A (5,7-dihydroxy-6- methoxy-2-phenyl-4-chromanone), Chrysin (5,7-dihydroxy-2-phenyl-4- chromanone), resveratrol ((E)-3,5,10-stilbenetriol), fenofibrate (methyl 2-[p-(p- chlorobenzoyl)phenoxy]-2-methylpropionate), GL-V9 (5-hydroxy-8-methoxy-2-30 phenyl-7-[4-(1-pyrrolidinyl)butoxy]-4-chromanone), Gen-27 (5-hydroxy-7-(2- hydroxy-3-piperidinopropoxy)-3-[p-(2-hydroxy-3-piperidinopropoxy)phenyl]-4- chromanone), Amentoflavone (8-[5-(5,7-dihydroxy-4-oxo-2-chromanyl)-2- hydroxyphenyl]-5,7-dihydroxy-2-(p-hydroxyphenyl)-4-chromenone), MJ ( methylDocket No. EPN-AC-RAFT.004PC PATENT {2-[(E)-2-pentenyl]-3-oxocyclopentyl}acetate), bufalin (5- {(1S,2S,5S,7R,10R,11R,14R,15R)-5,11-dihydroxy-2,15- dimethyltetracyclo[8.7.0.02,7.011,15]heptadec-14-yl}-2-pyranone), cryptotanshinone ((R,11(15)E)-6,6,14-trimethyl-12- 5 oxatetracyclo[8.7.0.02,7.011,15]heptadeca-1,7,9,11(15)-tetraene-16,17-dione), halofuginone (3-{3-[(2R,3S)-3-hydroxy-2-piperidyl]-2-oxopropyl}-7-bromo-6- chloro-3H-quinazolin-4-one), licochalcone A ((E)-3-[5-(1,1-dimethyl-2- propenyl)-4-hydroxy-2-methoxyphenyl]-1-(p-hydroxyphenyl)-2-propen-1-one), jolkinolide B ((1S,3R,8R,10R,11R,12R,17R)-5,12,16,16-tetramethyl-2,7,9- 10 trioxahexacyclo[9.8.0.01,3.04,8.08,10.012,17]nonadec-4-en-6-one), ORY-1001 ((1r,4r)-1-[(1R,2S)-2-phenylcyclopropylamino]-4-aminocyclohexane, ginsenoside 20(S)-Rg3 ((2R,3S,4S,5R,6R)-6-{(2R,5S,7R,10R,14S,15S,16R)-16-hydroxy-14- (1-hydroxy-1,5-dimethyl-4-hexenyl)-2,6,6,10,11- pentamethyltetracyclo[8.7.0.02,7.011,15]heptadec-5-yloxy}-5-[(2S,4R,5S,6R)-4,5-15 dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]-2- (hydroxymethyl)tetrahydro-2H-pyran-3,4-diol), 6913-0012 (ethyl 5-{(R)-3-[(R)- 1-(hydroxymethyl)propylamino]-2-methylpropoxy}-1-methyl-2-methyl-1H- indole-3-carboxylate), K263-0793 (N-3,4-dihydroxyphenyl{1-oxo-2-[(3- pyridyl)methyl]-2H-9-thia-2,4-diazafluoren-3-ylthio}acetamide), K611-0094 (N-20 (1,3-thiazol-2-yl)-2-[(N-m-nitrophenylcarbamoyl)methylthio]-4-amino-1,3- thiazole-5-carboxamide), D016-0099 (1-{5-[(S)-2-hydroxy-3- (phenethylamino)propoxy]-2-methyl-1H-indol-3-yl}-1-ethanone), K788-8853 (N- {[(S)-1-ethyl-2-pyrrolidinyl]methyl}-(E)-2-[(3,4-dimethoxyphenyl)methylene]-3- oxo-4H-1,4-benzothiazine-6-carboxamide), 4244-3659 ((S)-3-[(2,5- 25 dihydroxybenzoyl)methyl]-3-hydroxy-1-methyl-2-indolinone), AK-968 / 41922716 ({(E)-2-[(3,4-dichlorophenyl)methylene]hydrazino}(3,4,5- trihydroxyphenyl)methanone), AO-423 / 13128074 ((R)-3-benzylamino-1-(1- naphthyloxy)-2-propanol), AP-124 / 43383769 ((R)-3-benzylamino-1-(2-isopropyl- 5-methylphenoxy)-2-propanol), BrAcNHEtOP (N-bromoacetylethanolamine 30 phosphate), 3-PO (3-(3- pyridinyl)-1-(4-pyridinyl)-2-propen-1-one), PFK15 (l-(4- pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), or PFK-158 ((E)-1-(4- Pyridinyl)-3- [7-(trifluoromethyl)-2-quinolinyl]-2-propen-1-one), PQP ((E)-1- (3-pyridyl)-3-(2-quinolyl)-2-propen-1-one), KAN0436151 (4-[5-Chloro-4-(m-Docket No. EPN-AC-RAFT.004PC PATENT fluorophenyl)-2-thienylsulfonylamino]-2-hydroxybenzoic acid), KAN0436067 (m-(5-isopropyl-3-methyl-1-benzothiophen-2- ylsulfonylamino)benzoic acid), KAN0438757 (2-hydroxyethyl 4-(5'-fluoro-2'- hydroxy-3-biphenylylsulfonylamino)-2-hydroxybenzoate), or a salt thereof; 5 N4A (5,6,7,8-Tetrahydroxy-2-(p-hydroxyphenyl)-4-chromanone), YNl (7,8- Dihydroxy-3-(p-hydroxyphenyl)-4-chromanone), YZ29 (ethyl 7-hydroxy-3- coumarincarboxylate), AZ11 (N-[p-(2-amino-3-cyano-1-methyl-1H-indol-5- yloxy)phenyl]aminoacetamide), AZ44 (N-[p-(2-amino-3-cyano-1H-indol-5- yloxy)phenyl](S)-2-amino-3-hydroxypropionamide), AZ46 (N-[p-(2-amino-3-10 cyano-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ47 (N-[p-(2-amino-3- cyano-1-ethyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ48 (N-[p-(2- amino-3-cyano-1-isobutyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ49 (N-[p-(2-Amino-1-benzyl-3-cyano-1H-indol-5- yloxy)phenyl]aminoacetamide), AZ50 (N,N-dimethyl[2-amino-3-cyano-5-(p-15 glycylaminophenoxy)-1H-indol-1-yl]acetamide), AZ51 (N-[p-(3-cyano-1H- indol-5-yloxy)phenyl]aminoacetamide), AZ52 (N-[p-(3-cyano-1-ethyl-1H- indol-5-yloxy)phenyl]aminoacetamide), AZ53 (N-[p-(3-cyano-1-ethyl-1H- indol-5-yloxy)phenyl](methylamino)acetamide), AZ54 (N-[p-(3-cyano-1- ethyl-1H-indol-5-yloxy)phenyl](dimethylamino)acetamide, AZ55 (N-[p-(3- 20 cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ56 (N-[p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(R)-2- pyrrolidinecarboxamide), AZ57 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl]-N-methyl-(S)-2-pyrrolidinecarboxamide), AZ58 (N-[p-(3- cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(S)-2-azetidinecarboxamide), AZ5925 (N-[p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(S)-2- piperidinecarboxamide), AZ60 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl]-(S)-5-oxo-2-pyrrolidinecarboxamide), AZ61 (N-(p-{1-[(N- methylcarbamoyl)methyl]-3-cyano-1H-indol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ62 (N-(p-{3-cyano-1-[2-(dimethylamino)ethyl]-30 1H-indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide), AZ63 (N-(p-{3- cyano-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ64 (N-[p-(3-cyano-1-phenyl-1H-indol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ65 (N-{p-[3-cyano-1-(2-Docket No. EPN-AC-RAFT.004PC PATENT methyl-1-oxo-5-isoindolinyl)-1H-indol-5-yloxy]phenyl}-(S)-2- pyrrolidinecarboxamide), AZ66 (N-[p-(1-benzyl-3-cyano-1H-indol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ67 (N-(p-{3-cyano-1-[(3,5- dimethyl-4-isoxazolyl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2- 5 pyrrolidinecarboxamide), AZ26 (N-[p-(3-Cyano-1-isobutyl-1H-indol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ33 (N-(p-{3-cyano-1-[(3,5- dimethyl-4-isoxazolyl)methyl]-1H-indazol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ68 (N-[p-(3-cyano-1-isobutyl-1H-indazol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ69 (N-{p-[3-(1-methyl-1H-10 pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}aminoacetamide), AZ40 (N-{p-[3-(1- methyl-1H-pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}-(S)-2- pyrrolidinecarboxamide), AZ43 (N-{p-[1-methyl-3-(1-methyl-1H-pyrazol-4- yl)-1H-indol-5-yloxy]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ70 (N-[p-(3- cyano-1-isobutyl-1H-indol-5-ylamino)phenyl]-(S)-2-pyrrolidinecarboxamide),15 AZ71 (N-{p-[(3-cyano-1-isobutyl-1H-indol-5-yl)-N-methylamino]phenyl}- (S)-2-pyrrolidinecarboxamide), AZ72 (N-[p-(3-cyano-1-isobutyl-1H-indol-5- ylthio)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ73 (N-[p-(3-cyano-1- isobutyl-1H-indol-5-ylsulfonyl)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ74 (N-{p-[(3-Cyano-1-isobutyl-1H-indol-5-yl)methyl]phenyl}-(S)-2-20 pyrrolidinecarboxamide), formula 1(4-[4-(2H-1,3-benzodioxol-5-yl)-5-chloro- 2-thienylsulfonylamino]-2-hydroxybenzoic acid), formula 2 (2-Hydroxy-4- [m-(6-quinolyl)phenylsulfonylamino]benzoic acid), formula 3 (4-(2,5- dichloro-3-thienylsulfonylamino)-2-hydroxybenzoic acid), formula 4 (4-[5- chloro-4-(m-isopropoxycarbonylphenyl)-2-thienylsulfonylamino]-2-25 hydroxybenzoic acid), formula 5 (m-(5-isopropyl-3-methyl-1-benzofuran-2- ylsulfonylamino)benzoic acid), formula 6 ((3,5-dimethyl-1-benzothiophen-2- ylsulfonyl)[m-(1H-1,2,3,4-tetrazol-5-yl)phenyl]amine), formula 7 (m-(5- chloro-3-methyl-1-benzothiophen-2-ylsulfonylamino)benzoic acid), formula 8 ((5-Isopropyl-3-methyl-1-benzothiophen-2-ylsulfonyl)[m-(1H-1,2,3,4-30 tetrazol-5-yl)phenyl]amine), formula 9 (m-(3- biphenylylsulfonylamino)benzoic acid), formula 10 (2-(5-isopropyl-3-methyl- 1-benzothiophen-2-ylsulfonylamino)-4-methyl-1,3-thiazole-5-carboxylic acid), formula 11 (4-(5'-fluoro-2'-hydroxy-3-biphenylylsulfonylamino)-2-Docket No. EPN-AC-RAFT.004PC PATENT hydroxybenzoic acid), formula 12 (2-Hydroxyethyl 4-(5'-fluoro-2'-hydroxy-3- biphenylylsulfonylamino)-2-hydroxybenzoate), formula 13 ([4- (methylsulfonyl)-3-pyridyl][8-(1-methyl-1H-indol-6-yl)-6- quinoxalinyl]amine) formula 14 (N-(tetrahydro-2H-pyran-4-yl)-3-[8-(1- 5 methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 15 ([4- (methylsulfonyl)-3-pyridyl][8-(3-methyl-1-benzothiophen-5-yl)-6- quinoxalinyl]amine), formula 16 (N-[(1-Methyl-3-pyrrolidinyl)methyl]-3-[8- (1-methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 17 (5-{3-[8-(1-Methyl-1H-indol-6-yl)-6-quinoxalinylamino]-4-10 pyridylsulfonylamino}pyrimidine), formula 18 (N-5-pyrimidinyl-3-[8-(1- methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 19 (N- (1-Methyl-3-piperidyl)-3-[8-(1-methyl-1H-indol-6-yl)-6- quinoxalinylamino]isonicotinamide), formula 20 (N-(1-Methyl-3- pyrrolidinyl)-3-[8-(4-fluoro-1-methyl-1H-indol-6-yl)-6-15 quinoxalinylamino]isonicotinamide), formula 21 ([(S)-(6-Methoxy-3- pyridyl)(3-methyl-3H-1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)- 6-quinoxalinyl]amine), formula 22 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3- methyl-3H-1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)-6- quinoxalinyl]amine), formula 23 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3-methyl-20 3H-1,2,3-triazol-4-yl)methyl][8-(3-methyl-1-benzofuran-5-yl)-6- quinoxalinyl]amine), formula 24 (5-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)- 4-bromo-2-phenyl-2H-pyridazin-3-one), formula 25 (5-(4-acetyl-5-methyl- 1H-1,2,3-triazol-1-yl)-4-iodo-2-phenyl-2H-pyridazin-3-one), formula 26 (5- (4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-2-benzyl-4-bromo-2H-pyridazin-3-25 one), formula 27 (5-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-bromo-2- phenethyl-2H-pyridazin-3-one), formula 28 (5-(4-acetyl-5-methyl-1H-1,2,3- triazol-1-yl)-4-bromo-2-(p-chlorophenyl)-2H-pyridazin-3-one), formula 29 (3- (p-bromophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza-4-indenone), formula 30 (3-(p-chlorophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza-4-30 indenone), formula 31 (1-(p-methoxyphenyl)-3-(p-methoxyphenyl)-1,3a,5,6- tetrahydro-1,5,7-triaza-4-indenone), formula 32 (1-(p-bromophenyl)-3-phenyl- 1,3a,5,6-tetrahydro-1,5,7-triaza-4-indenone), formula 33 ({5- azatricyclo[7.4.0.02,6]trideca-1(13),2(6),3,7,9,11-hexaen-4-Docket No. EPN-AC-RAFT.004PC PATENT yl}phenylmethanone), formula 34 ({5-azatricyclo[7.4.0.02,6]trideca- 1(13),2(6),3,7,9,11-hexaen-4-yl}(4-pyridyl)methanone hydrochloride), formula 35 ((p-aminophenyl){5-azatricyclo[7.4.0.02,6]trideca- 1(13),2(6),3,7,9,11-hexaen-4-yl}methanone), formula 36 ([(S)-1-(m- 5 methoxyphenyl)ethyl][6-(1,3-benzothiazol-6-yl)-2-methyl-4- pyrimidinyl]amine), Compound 5 (N-{p-[p- (dimethylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 7 (N-[p-(p-morpholinophenoxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 8 (N-[p-(p-piperidinophenoxy)phenyl]-(S)-2-10 pyrrolidinecarboxamide), compound 9 (N-{p-[p-(1- pyrrolidinyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 11 (N-{p-[p-(diethylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 12 (N-{p-[p-(dipropylamino)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 13 (N-{p-[p- 15 (diallylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 14 (N-{p-[p-(1H-imidazol-1-yl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 15 (N-{p-[p-(4-pyridyl)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 16 (N-[p-(4-biphenylyloxy)phenyl]-(S)- 2-pyrrolidinecarboxamide), compound 18 (N-{p-[p- 20 (morpholinomethyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 22 (N-[p-(5,6,7,8-tetrahydro-2-naphthyloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 27 (N-{p-[p- (trifluoromethyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 28 (N-[p-(p-chlorophenoxy)phenyl]-(S)-2-pyrrolidinecarboxamide), 25 compound 29 (N-[p-(2-naphthyloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 30 (N-[p-(p-cumenyloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 32 (N-[p-(p-ethoxyphenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 33 (N-[p-(p-methoxyphenoxy)phenyl]- (S)-2-pyrrolidinecarboxamide), (E)-3-(p-chlorophenyl)-1-(3-pyridyl)-2-30 propen-1-one, (E)-3-(1-naphthyl)-1-(4-pyridyl)-2-propen-1-one, N-{p-[(E)-2- isonicotinoyl-1-ethenyl]phenyl}acetamide, (E)-3-(o-chlorophenyl)-1-(2- pyridyl)-2-propen-1-one, (E)-3-(o-chlorophenyl)-1-(3-pyridyl)-2-propen-1- one, Shikonin (2-[(S)-1-hydroxy-4-methyl-3-pentenyl]-2,3-dihydro-1,4-Docket No. EPN-AC-RAFT.004PC PATENT naphthalenedione), metformin (3-(azanylazanylidenemethyl)-1,1- dimethylguanidine), VK3 (2-methyl-1,4-naphthalenedione), VK5 (4-amino-2- methyl-1-naphthol), Lapachol (3-hydroxy-2-(3-methyl-2-butenyl)-2,3- dihydro-1,4-naphthalenedione), C3k ((3-methyl-1,4-dioxo-2,3-dihydro-2- 5 naphthyl)methyl 1-piperidinecarbodithioate, benzoxepane ((E)-4-[2-(p- ethylphenyl)ethylidene]-6,8-dimethoxy-2,3-dihydro-1-benzoxepin-5-one), PB2 ((2R,3R,4R,2'R,3'R)-2,2'-bis(3,4-xylyl)-4,8'-bichromane-3,3',5,5',7,7'- hexol), Parthenolide (2-[2-(1-{(1S,2R,4R,5S,11S,E)-5-methyl-12-methylene- 13-oxo-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-8-10 yl}ethenyloxy)ethoxy]ethyl (1S,2S,4R,10S,E)-4-methyl-11-methylene-12- oxo-3,13-dioxatricyclo[8.3.0.02,4]tridec-7-ene-8-carboxylate), benserazide (2- amino-3-hydroxy-1-{2-[(2,3,4-trihydroxyphenyl)methyl]hydrazino}-1- propanone, ML-265 (10-[(m-aminophenyl)methyl]-7-methyl-4- (methylsulfinyl)-3-thia-7,10,11-triazatricyclo[6.4.0.02,6]dodeca-15 1(8),2(6),4,11-tetraen-9-one, PKL-IN-1 (compound 12a: 2,3,5,6,7- Pentahydroxy-10H-9-oxa-10λ6-thiaphenanthrene-10,10-dione), PKM2-IN-6 (compound 7d: [4-(1,3a-diaza-3-indenyl)-1,3-thiazol-2-yl](o- methoxyphenyl)amine), PKM2-IN-3 ((E)-4-[(p-ethylphenyl)methylene]-6,8- dimethoxy-2,3-dihydro-1-benzoxepin-5-one), CIAC001 (2-[(3S,4R)-p- 20 mentha-1,8-dien-3-yl]-5-[1-(2H-1,2,3-triazol-2-yl)ethyl]resorcinol), vitamin K5 (4-amino-2-methyl-1-naphthol), Alkannin (6-[(S)-1-hydroxy-4-methyl-3- pentenyl]-5,8-dihydroxy-1,4-naphthalenedione), PKM2 / PDK1-IN-1 (N-{(R)- 2-[(R)-1-(5,8-dihydroxy-1,4-dioxo-2-naphthyl)-4-methyl-3-pentenylthio]-1- methylethyl}5-[(4R)-2-(o-tolyl)-1,3-dithian-4-yl]valeramide, PKM2-IN-5 (N-25 isopropyl-12-methyl-7-oxo-8-oxa-3-thiatricyclo[7.4.0.02,6]trideca- 1(13),2(6),4,9,11-pentaene-4-carboxamide, PKM2-IN-4 (Methyl 3-bromo-2- (1-hydroxycyclohexyl)-1-selena-7aλ5-aza-5-indenecarboxylate), ellagic acid, silybin, Gossypol (1-[8'-acetyl-1,1',6,6',7'-pentahydroxy-5,5'-bis(isopropyl)-3,3',7- trimethyl-2,2'-binaphthyl-8-yl]-1-ethanone), FX-11 (7-benzyl-2,3-dihydroxy-6-30 methyl-4-propyl-1-naphthoic acid), Galloflavin (2,5,6,7-tetrahydroxy-4,10-dioxa- 3,9-phenanthrenedione), oxamate, Morin (2-(2,4-dihydroxyphenyl)-3,5,7- trihydroxy-4-chromenone), Epigallocatechin gallate ((2R,3R)-2-(3,4,5- trihydroxyphenyl)-3,5,7-chromantriol), GSK2837808A (5-[3-Docket No. EPN-AC-RAFT.004PC PATENT (Cyclopropylaminosulfonyl)-7-(2,4-dimethoxy-5-pyrimidinyl)-4-quinolylamino]- 3-(3,5-difluorophenoxy)benzoic acid), GNE-140 (3-(o-Chlorophenylthio)-4- hydroxy-6-(p-morpholinophenyl)-6-(3-thienyl)-5,6-dihydro-1H-pyridin-2-one), AXKO-0046 (1-({[3-(2-benzylaminoethyl)-1H-indol-2- 5 yl]methyl}amino)cycloheptane), LDHA-IN-3 (compound 2: trifluoro[p- (phenylseleno)phenyl]methane), NHI-2 (methyl 1-hydroxy-6-phenyl-4- (trifluoromethyl)-1H-indole-2-carboxylate), LDHA-IN-4 (AZ33: [(p-{3-[N-2-(N- 2-Methyl-1,3-benzothiazol-6- ylcarbamoyl)ethylcarbamoyl]propyl}phenyl)methyl]malonic acid), LM021 ((E)- 10 3-[p-(dimethylamino)phenyl]-1-(4-hydroxy-3-coumarinyl)-2-propen-1-one), LDH-IN-1 (2-{4-[(p-aminosulfophenyl)methyl]-3-(3-biphenylyl)-5- (cyclopropylmethyl)-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid), Nifurtimox ((E)-[(5-nitro-2-furyl)methylene](3-methyl-1,1-dioxo-1λ6,4-thiazinan- 4-yl)amine), 3-dehydrotrametenolic acid ((R)-2-{(2S,5S,7R,11R,14S,15R)-5-15 hydroxy-2,6,6,11,15-pentamethyltetracyclo[8.7.0.02,7.011,15]heptadeca-1(17),9- dien-14-yl}-6-methyl-5-heptenoic acid), CHK-336 (example 1: 2-{4-[(4- aminosulfo-3-fluorophenyl)methyl]-5-(cyclopropylmethyl)-3-(p-fluorophenyl)- 1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid), Glomeratose A ((2S,3S,4R,5R)- 2-[(2R,3R,4S,5S,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-yloxy]-4-20 hydroxy-2,5-bis(hydroxymethyl)tetrahydro-3-furyl (E)-3-(3,4,5- trimethoxyphenyl)acrylate), anticancer agent 121 (methyl (Z)-3-[3-(p- methoxyphenyl)-4-phenyl-3H-1,3-thiazol-2-ylidene]propionate), anticancer agent 122 (methyl (Z)-3-[3-(p-chlorophenyl)-4-phenyl-3H-1,3-thiazol-2- ylidene]propionate), RS6212 (3-{4-[(6-oxo-4,5-diaza-5-indanyl)methyl]-1-25 piperidyl}-1H-1λ6,2-benzisothiazole-1,1-dione), antibiofilm agent 5 (ethyl 6-({4- [2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]-1-piperazinyl}methyl)-4- (2-butyl-5-chloro-3H-imidazol-4-yl)-2-oxo-3,4-dihydro-1H-pyrimidine-5- carboxylate), LDHA-IN-6 (compound 6: methyl 3-{N-p-[(1-methyl-1H-imidazol- 2-yl)carbonyl]phenylcarbamoyl}-2-[p-(trifluoromethyl)phenyl]propionate),30 LDHA-IN-7, the corresponding carboxylic acid of LDHA-IN-6 (compound 21: 3- {N-p-[(1-Methyl-1H-imidazol-2-yl)carbonyl]phenylcarbamoyl}-2-[p- (trifluoromethyl)phenyl]propionic acid), NCATS-SM1441 (2-{4-[(4-Aminosulfo- 3-fluorophenyl)methyl]-5-(cyclopropylmethyl)-3-{m-[2-(5-methyl-2-Docket No. EPN-AC-RAFT.004PC PATENT thienyl)ethynyl]phenyl}-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid), ceritinib (LDK378: 5-chloro-2-[2-isopropoxy-4-(4-piperidyl)-5-toluidino]-4-[o- (isopropylsulfonyl)phenylamino]pyrimidine), linsitinib (OSI-906): (1s,3s)-3-[7- amino-1-(2-phenyl-7-quinolyl)-2,3a,6-triaza-3-indenyl]-1-methylcyclobutanol), 5 picropodophyllin ((10R,11S,15R,16S)-11,15,16-trimethyl-10-(3,4,5- trimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8- trien-12-one), PQ401 (3-(5-chloro-2-methoxyphenyl)-1-(2-methyl-4- quinolyl)urea), BMS-754807 (N-(6-fluoro-3-pyridyl)-(S)-1-[7-(5-cyclopropyl-1H- pyrazol-3-ylamino)-3a,4,6-triaza-5-indenyl]-2-methyl-2-pyrrolidinecarboxamide),10 NVP-AEW541 ((R)-3-{3-[(1-azetidinyl)methyl]-1-azetidinyl}-1-[m- (benzyloxy)phenyl]-3H-4,6-diazainden-7-ylamine), BMS936524 (3-[(S)-2-(m- chlorophenyl)-2-hydroxyethylamino]-2-(5-morpholino-1H-1,3-benzimidazol-2- yl)-2,4-cyclohexadien-1-one), AZD-3463 (2-[4-(4-amino-1-piperidyl)-2- anisidino]-5-chloro-4-(1H-indol-3-yl)pyrimidine), GSK1838705A (N-methyl-2-15 (6-{1-[2-(dimethylamino)acetyl]-5-methoxy-6-indolinylamino}-1H-1,5,7- triazainden-4-ylamino)-6-fluorobenzamide), GSK1904529A (N-2,6- difluorophenyl5-{3-[2-(5-ethyl-2-methoxy-4-{4-[4-(methylsulfonyl)-1- piperazinyl]-1-piperidyl}phenylamino)-4-pyrimidinyl]-1,3a-diaza-2-indenyl}-2- anisamide), NBI-31772 (6,7-dihydroxy-4-protocatechuoyl-2-naphthoic acid),20 NVP-TAE 226 (N-methyl-o-[5-chloro-2-(2-methoxy-4-morpholinophenylamino)- 4-pyrimidinylamino]benzamide), XL228 (4-(5-cyclopropyl-1H-pyrazol-3- ylamino)-2-{[(3-isopropyl-5-isoxazolyl)methyl]amino}-6-(4-methyl-1- piperazinyl)pyrimidine), AG1024 ({[3-bromo-5-(tert-butyl)-4- hydroxyphenyl]methylene}propanedinitrile), chromeceptin (2-amino-7- 25 (dimethylamino)-4-[m-(trifluoromethyl)phenyl]-4H-chromene-3-carbonitrile), Indirubin derivative E804 ((Z)-3-(3,4-dihydroxybutoxyimino)-2,3'-biindolin-2'- one), AZ7550 (N-(2-{N-methyl[2-(methylamino)ethyl]amino}-4-methoxy-5-{[4- (1-methyl-1H-indol-3-yl)-2-pyrimidinyl]methyl}phenyl)acrylamide), I-OMe tyrphostin AG538 ((E)-[(4-hydroxy-3-iodo-5-30 methoxyphenyl)methylene]protocatechuoylacetonitrile, IGF1R inhibitor 2 (6- fluoro-2-[6-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-7-isoquinolylamino)-1H- 1,5,7-triazainden-4-ylamino]benzamide), AG538 ((E)-[(3,4- dihydroxyphenyl)methylene]protocatechuoylacetonitrile), AZ12253801 ((5-Docket No. EPN-AC-RAFT.004PC PATENT cyclopropyl-1H-pyrazol-3-yl)(2-{(S)-2-methyl-2-[3-(2-pyridyl)-5-isoxazolyl]-1- pyrrolidinyl}-6-methyl-4-pyrimidinyl)amine, IGF-1R / SRC-IN-1 (N-(p- tolyl)methyl(1H-indol-3-yl)oxoacetamide), IGF1-R inhibitor 3 (N-{1-[4-(6-cyano- 1H-indol-3-yl)butyl]-4-piperidyl}-3-cyano-5-fluoro-1H-indole-7-carboxamide, 5 BMS695735 (4-[2-(4-chloro-1H-pyrazol-1-yl)ethylamino]-3-{5-[1-(3- fluoropropyl)-4-piperidyl]-7-methyl-1H-1,3-benzimidazol-2-yl}-1H-pyridin-2- one), chimaphilin (2,7-Dimethyl-1,4-naphthalenedione), SU4343 ((Z)-3-[(p- cumenyl)methylene]-2-indolinone), and salts thereof. 10 9. The method of claim 4 wherein the PFKFB3 inhibitor is selected from the group consisting of P1 ((S)-2-[(S)-2-[(S)-2-{(S)-2-[(S)-2-Amino-3- hydroxypropionylamino]-3-phenylpropionylamino}-4-methylvalerylamino]-4- methylvalerylamino]-6-amidinohexanamide), P2 ((R)-2-({[(R)-2-Amino-3- (1H-indol-3-yl)propionylamino]methyl}carbonylamino)-3-(p-15 hydroxyphenyl)propionic acid), P3 ((2S,3R)-2-[(S)-2-[(S)-2-[({(S)-2-[(S)-2- Amino-3-(p-hydroxyphenyl)propionylamino]-3- hydroxypropionylamino}methyl)carbonylamino]-3-phenylpropionylamino]-4- methylvalerylamino]-3-hydroxybutyric acid), BrAcNHEtOP (N- bromoacetylethanolamine phosphate), 3-PO (3-(3- pyridinyl)-1-(4-pyridinyl)- 20 2-propen-1-one), PFK15 (l-(4- pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), or PFK-158 ((E)-1-(4-Pyridinyl)-3- [7-(trifluoromethyl)-2-quinolinyl]-2- propen-1-one), PQP ((E)-1-(3-pyridyl)-3-(2-quinolyl)-2-propen-1-one), KAN0436151 (4-[5-Chloro-4-(m-fluorophenyl)-2-thienylsulfonylamino]-2- hydroxybenzoic acid), KAN0436067 (m-(5-isopropyl-3-methyl-1-25 benzothiophen-2-ylsulfonylamino)benzoic acid), KAN0438757 (2- hydroxyethyl 4-(5'-fluoro-2'-hydroxy-3-biphenylylsulfonylamino)-2- hydroxybenzoate), or a salt thereof; N4A (5,6,7,8-Tetrahydroxy-2-(p- hydroxyphenyl)-4-chromanone), YNl (7,8-Dihydroxy-3-(p-hydroxyphenyl)-4- chromanone), YZ29 (ethyl 7-hydroxy-3-coumarincarboxylate), AZ11 (N-[p- 30 (2-amino-3-cyano-1-methyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ44 (N-[p-(2-amino-3-cyano-1H-indol-5-yloxy)phenyl](S)-2-amino-3- hydroxypropionamide), AZ46 (N-[p-(2-amino-3-cyano-1H-indol-5- yloxy)phenyl]aminoacetamide), AZ47 (N-[p-(2-amino-3-cyano-1-ethyl-1H-Docket No. EPN-AC-RAFT.004PC PATENT indol-5-yloxy)phenyl]aminoacetamide), AZ48 (N-[p-(2-amino-3-cyano-1- isobutyl-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ49 (N-[p-(2-Amino- 1-benzyl-3-cyano-1H-indol-5-yloxy)phenyl]aminoacetamide), AZ50 (N,N- dimethyl[2-amino-3-cyano-5-(p-glycylaminophenoxy)-1H-indol-1- 5 yl]acetamide), AZ51 (N-[p-(3-cyano-1H-indol-5- yloxy)phenyl]aminoacetamide), AZ52 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl]aminoacetamide), AZ53 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl](methylamino)acetamide), AZ54 (N-[p-(3-cyano-1-ethyl-1H- indol-5-yloxy)phenyl](dimethylamino)acetamide, AZ55 (N-[p-(3-cyano-1-10 ethyl-1H-indol-5-yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ56 (N-[p- (3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(R)-2-pyrrolidinecarboxamide), AZ57 (N-[p-(3-cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-N-methyl-(S)-2- pyrrolidinecarboxamide), AZ58 (N-[p-(3-cyano-1-ethyl-1H-indol-5- yloxy)phenyl]-(S)-2-azetidinecarboxamide), AZ59 (N-[p-(3-cyano-1-ethyl-15 1H-indol-5-yloxy)phenyl]-(S)-2-piperidinecarboxamide), AZ60 (N-[p-(3- cyano-1-ethyl-1H-indol-5-yloxy)phenyl]-(S)-5-oxo-2- pyrrolidinecarboxamide), AZ61 (N-(p-{1-[(N-methylcarbamoyl)methyl]-3- cyano-1H-indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide), AZ62 (N- (p-{3-cyano-1-[2-(dimethylamino)ethyl]-1H-indol-5-yloxy}phenyl)-(S)-2-20 pyrrolidinecarboxamide), AZ63 (N-(p-{3-cyano-1-[(tetrahydro-2H-pyran-4- yl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide), AZ64 (N-[p-(3-cyano-1-phenyl-1H-indol-5-yloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), AZ65 (N-{p-[3-cyano-1-(2-methyl-1-oxo-5- isoindolinyl)-1H-indol-5-yloxy]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ6625 (N-[p-(1-benzyl-3-cyano-1H-indol-5-yloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), AZ67 (N-(p-{3-cyano-1-[(3,5-dimethyl-4- isoxazolyl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide), AZ26 (N-[p-(3-Cyano-1-isobutyl-1H-indol-5-yloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), AZ33 (N-(p-{3-cyano-1-[(3,5-dimethyl-4-30 isoxazolyl)methyl]-1H-indazol-5-yloxy}phenyl)-(S)-2- pyrrolidinecarboxamide), AZ68 (N-[p-(3-cyano-1-isobutyl-1H-indazol-5- yloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ69 (N-{p-[3-(1-methyl-1H- pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}aminoacetamide), AZ40 (N-{p-[3-(1-Docket No. EPN-AC-RAFT.004PC PATENT methyl-1H-pyrazol-4-yl)-1H-indol-5-yloxy]phenyl}-(S)-2- pyrrolidinecarboxamide), AZ43 (N-{p-[1-methyl-3-(1-methyl-1H-pyrazol-4- yl)-1H-indol-5-yloxy]phenyl}-(S)-2-pyrrolidinecarboxamide), AZ70 (N-[p-(3- cyano-1-isobutyl-1H-indol-5-ylamino)phenyl]-(S)-2-pyrrolidinecarboxamide), 5 AZ71 (N-{p-[(3-cyano-1-isobutyl-1H-indol-5-yl)-N-methylamino]phenyl}- (S)-2-pyrrolidinecarboxamide), AZ72 (N-[p-(3-cyano-1-isobutyl-1H-indol-5- ylthio)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ73 (N-[p-(3-cyano-1- isobutyl-1H-indol-5-ylsulfonyl)phenyl]-(S)-2-pyrrolidinecarboxamide), AZ74 (N-{p-[(3-Cyano-1-isobutyl-1H-indol-5-yl)methyl]phenyl}-(S)-2-10 pyrrolidinecarboxamide), formula 1 (4-[4-(2H-1,3-benzodioxol-5-yl)-5- chloro-2-thienylsulfonylamino]-2-hydroxybenzoic acid), formula 2 (2- Hydroxy-4-[m-(6-quinolyl)phenylsulfonylamino]benzoic acid), formula 3 (4- (2,5-dichloro-3-thienylsulfonylamino)-2-hydroxybenzoic acid), formula 4 (4- [5-chloro-4-(m-isopropoxycarbonylphenyl)-2-thienylsulfonylamino]-2-15 hydroxybenzoic acid), formula 5 (m-(5-isopropyl-3-methyl-1-benzofuran-2- ylsulfonylamino)benzoic acid), formula 6 ((3,5-dimethyl-1-benzothiophen-2- ylsulfonyl)[m-(1H-1,2,3,4-tetrazol-5-yl)phenyl]amine), formula 7 (m-(5- chloro-3-methyl-1-benzothiophen-2-ylsulfonylamino)benzoic acid), formula 8 ((5-Isopropyl-3-methyl-1-benzothiophen-2-ylsulfonyl)[m-(1H-1,2,3,4-20 tetrazol-5-yl)phenyl]amine), formula 9 (m-(3- biphenylylsulfonylamino)benzoic acid), formula 10 (2-(5-isopropyl-3-methyl- 1-benzothiophen-2-ylsulfonylamino)-4-methyl-1,3-thiazole-5-carboxylic acid), formula 11 (4-(5'-fluoro-2'-hydroxy-3-biphenylylsulfonylamino)-2- hydroxybenzoic acid), formula 12 (2-Hydroxyethyl 4-(5'-fluoro-2'-hydroxy-3-25 biphenylylsulfonylamino)-2-hydroxybenzoate), formula 13 ([4- (methylsulfonyl)-3-pyridyl][8-(1-methyl-1H-indol-6-yl)-6- quinoxalinyl]amine) formula 14 (N-(tetrahydro-2H-pyran-4-yl)-3-[8-(1- methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 15 ([4- (methylsulfonyl)-3-pyridyl][8-(3-methyl-1-benzothiophen-5-yl)-6-30 quinoxalinyl]amine), formula 16 (N-[(1-Methyl-3-pyrrolidinyl)methyl]-3-[8- (1-methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 17 (5-{3-[8-(1-Methyl-1H-indol-6-yl)-6-quinoxalinylamino]-4- pyridylsulfonylamino}pyrimidine), formula 18 (N-5-pyrimidinyl-3-[8-(1-Docket No. EPN-AC-RAFT.004PC PATENT methyl-1H-indol-6-yl)-6-quinoxalinylamino]isonicotinamide), formula 19 (N- (1-Methyl-3-piperidyl)-3-[8-(1-methyl-1H-indol-6-yl)-6- quinoxalinylamino]isonicotinamide), formula 20 (N-(1-Methyl-3- pyrrolidinyl)-3-[8-(4-fluoro-1-methyl-1H-indol-6-yl)-6- 5 quinoxalinylamino]isonicotinamide), formula 21 ([(S)-(6-Methoxy-3- pyridyl)(3-methyl-3H-1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)- 6-quinoxalinyl]amine), formula 22 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3- methyl-3H-1,2,3-triazol-4-yl)methyl][8-(1-methyl-1H-indol-6-yl)-6- quinoxalinyl]amine), formula 23 ([(S)-(1-Methyl-1H-pyrazol-4-yl)(3-methyl-10 3H-1,2,3-triazol-4-yl)methyl][8-(3-methyl-1-benzofuran-5-yl)-6- quinoxalinyl]amine), formula 24 (5-(4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)- 4-bromo-2-phenyl-2H-pyridazin-3-one), formula 25 (5-(4-acetyl-5-methyl- 1H-1,2,3-triazol-1-yl)-4-iodo-2-phenyl-2H-pyridazin-3-one), formula 26 (5- (4-acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-2-benzyl-4-bromo-2H-pyridazin-3-15 one), formula 27 (5-(4-Acetyl-5-methyl-1H-1,2,3-triazol-1-yl)-4-bromo-2- phenethyl-2H-pyridazin-3-one), formula 28 (5-(4-acetyl-5-methyl-1H-1,2,3- triazol-1-yl)-4-bromo-2-(p-chlorophenyl)-2H-pyridazin-3-one), formula 29 (3- (p-bromophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza-4-indenone), formula 30 (3-(p-chlorophenyl)-1-phenyl-1,3a,5,6-tetrahydro-1,5,7-triaza-4-20 indenone), formula 31 (1-(p-methoxyphenyl)-3-(p-methoxyphenyl)-1,3a,5,6- tetrahydro-1,5,7-triaza-4-indenone), formula 32 (1-(p-bromophenyl)-3-phenyl- 1,3a,5,6-tetrahydro-1,5,7-triaza-4-indenone), formula 33 ({5- azatricyclo[7.4.0.02,6]trideca-1(13),2(6),3,7,9,11-hexaen-4- yl}phenylmethanone), formula 34 ({5-azatricyclo[7.4.0.02,6]trideca- 25 1(13),2(6),3,7,9,11-hexaen-4-yl}(4-pyridyl)methanone hydrochloride), formula 35 ((p-aminophenyl){5-azatricyclo[7.4.0.02,6]trideca- 1(13),2(6),3,7,9,11-hexaen-4-yl}methanone), formula 36 ([(S)-1-(m- methoxyphenyl)ethyl][6-(1,3-benzothiazol-6-yl)-2-methyl-4- pyrimidinyl]amine), Compound 5 (N-{p-[p- 30 (dimethylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 7 (N-[p-(p-morpholinophenoxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 8 (N-[p-(p-piperidinophenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 9 (N-{p-[p-(1-Docket No. EPN-AC-RAFT.004PC PATENT pyrrolidinyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 11 (N-{p-[p-(diethylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 12 (N-{p-[p-(dipropylamino)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 13 (N-{p-[p- 5 (diallylamino)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 14 (N-{p-[p-(1H-imidazol-1-yl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 15 (N-{p-[p-(4-pyridyl)phenoxy]phenyl}-(S)-2- pyrrolidinecarboxamide), compound 16 (N-[p-(4-biphenylyloxy)phenyl]-(S)- 2-pyrrolidinecarboxamide), compound 18 (N-{p-[p- 10 (morpholinomethyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 22 (N-[p-(5,6,7,8-tetrahydro-2-naphthyloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 27 (N-{p-[p- (trifluoromethyl)phenoxy]phenyl}-(S)-2-pyrrolidinecarboxamide), compound 28 (N-[p-(p-chlorophenoxy)phenyl]-(S)-2-pyrrolidinecarboxamide), 15 compound 29 (N-[p-(2-naphthyloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 30 (N-[p-(p-cumenyloxy)phenyl]-(S)-2-pyrrolidinecarboxamide), compound 32 (N-[p-(p-ethoxyphenoxy)phenyl]-(S)-2- pyrrolidinecarboxamide), compound 33 (N-[p-(p-methoxyphenoxy)phenyl]- (S)-2-pyrrolidinecarboxamide), (E)-3-(p-chlorophenyl)-1-(3-pyridyl)-2-20 propen-1-one, (E)-3-(1-naphthyl)-1-(4-pyridyl)-2-propen-1-one, N-{p-[(E)-2- isonicotinoyl-1-ethenyl]phenyl}acetamide, (E)-3-(o-chlorophenyl)-1-(2- pyridyl)-2-propen-1-one, (E)-3-(o-chlorophenyl)-1-(3-pyridyl)-2-propen-1- one, and salts thereof. 25 11. The method of claim 5 wherein the an inhibitor of insulin growth factor receptor type 1 (IGF1R) signaling is selected from the group consisting of teprotumumab, MK-0646, MM-141, ganitumab (AMG479), xentuzumab, figitumumab, dalotuzumab, robatumumab (Sch 717454), dusigitumab (MEDI 573), veligrotug, istiratumab, ceritinib (LDK378: 5-chloro-2-[2-isopropoxy-4-(4- 30 piperidyl)-5-toluidino]-4-[o-(isopropylsulfonyl)phenylamino]pyrimidine), linsitinib (OSI-906): (1s,3s)-3-[7-amino-1-(2-phenyl-7-quinolyl)-2,3a,6-triaza-3- indenyl]-1-methylcyclobutanol), picropodophyllin ((10R,11S,15R,16S)-11,15,16- trimethyl-10-(3,4,5-trimethoxyphenyl)-4,6,13-Docket No. EPN-AC-RAFT.004PC PATENT trioxatetracyclo[7.7.0.03,7.011,15]hexadeca-1,3(7),8-trien-12-one), PQ401 (3-(5- chloro-2-methoxyphenyl)-1-(2-methyl-4-quinolyl)urea), BMS-754807 (N-(6- fluoro-3-pyridyl)-(S)-1-[7-(5-cyclopropyl-1H-pyrazol-3-ylamino)-3a,4,6-triaza-5- indenyl]-2-methyl-2-pyrrolidinecarboxamide), NVP-AEW541 ((R)-3-{3-[(1- 5 azetidinyl)methyl]-1-azetidinyl}-1-[m-(benzyloxy)phenyl]-3H-4,6-diazainden-7- ylamine), BMS936524 (3-[(S)-2-(m-chlorophenyl)-2-hydroxyethylamino]-2-(5- morpholino-1H-1,3-benzimidazol-2-yl)-2,4-cyclohexadien-1-one), AZD-3463 (2- [4-(4-amino-1-piperidyl)-2-anisidino]-5-chloro-4-(1H-indol-3-yl)pyrimidine), GSK1838705A (N-methyl-2-(6-{1-[2-(dimethylamino)acetyl]-5-methoxy-6- 10 indolinylamino}-1H-1,5,7-triazainden-4-ylamino)-6-fluorobenzamide), GSK1904529A (N-2,6-difluorophenyl5-{3-[2-(5-ethyl-2-methoxy-4-{4-[4- (methylsulfonyl)-1-piperazinyl]-1-piperidyl}phenylamino)-4-pyrimidinyl]-1,3a- diaza-2-indenyl}-2-anisamide), NBI-31772 (6,7-dihydroxy-4-protocatechuoyl-2- naphthoic acid), NVP-TAE 226 (N-methyl-o-[5-chloro-2-(2-methoxy-4-15 morpholinophenylamino)-4-pyrimidinylamino]benzamide), XL228 (4-(5- cyclopropyl-1H-pyrazol-3-ylamino)-2-{[(3-isopropyl-5- isoxazolyl)methyl]amino}-6-(4-methyl-1-piperazinyl)pyrimidine), AG1024 ({[3- bromo-5-(tert-butyl)-4-hydroxyphenyl]methylene}propanedinitrile), chromeceptin (2-amino-7-(dimethylamino)-4-[m-(trifluoromethyl)phenyl]-4H-chromene-3-20 carbonitrile), Indirubin derivative E804 ((Z)-3-(3,4-dihydroxybutoxyimino)-2,3'- biindolin-2'-one), AZ7550 (N-(2-{N-methyl[2-(methylamino)ethyl]amino}-4- methoxy-5-{[4-(1-methyl-1H-indol-3-yl)-2- pyrimidinyl]methyl}phenyl)acrylamide), I-OMe tyrphostin AG538 ((E)-[(4- hydroxy-3-iodo-5-methoxyphenyl)methylene]protocatechuoylacetonitrile, IGF1R25 inhibitor 2 (6-fluoro-2-[6-(6-methoxy-2-methyl-1,2,3,4-tetrahydro-7- isoquinolylamino)-1H-1,5,7-triazainden-4-ylamino]benzamide), AG538 ((E)- [(3,4-dihydroxyphenyl)methylene]protocatechuoylacetonitrile), AZ12253801 ((5- cyclopropyl-1H-pyrazol-3-yl)(2-{(S)-2-methyl-2-[3-(2-pyridyl)-5-isoxazolyl]-1- pyrrolidinyl}-6-methyl-4-pyrimidinyl)amine, IGF-1R / SRC-IN-1 (N-(p-30 tolyl)methyl(1H-indol-3-yl)oxoacetamide), IGF1-R inhibitor 3 (N-{1-[4-(6-cyano- 1H-indol-3-yl)butyl]-4-piperidyl}-3-cyano-5-fluoro-1H-indole-7-carboxamide, BMS695735 (4-[2-(4-chloro-1H-pyrazol-1-yl)ethylamino]-3-{5-[1-(3- fluoropropyl)-4-piperidyl]-7-methyl-1H-1,3-benzimidazol-2-yl}-1H-pyridin-2-Docket No. EPN-AC-RAFT.004PC PATENT one), chimaphilin (2,7-Dimethyl-1,4-naphthalenedione), SU4343 ((Z)-3-[(p- cumenyl)methylene]-2-indolinone), and salts thereof.

12. The method of claim 3 wherein the glycolysis inhibitor is selected from the 5 group consisting of 3-PO (3-(3- pyridinyl)-1-(4-pyridinyl)-2-propen-1-one), PFK15 (l-(4- pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), or PFK-158 ((E)- 1-(4-Pyridinyl)-3- [7-(trifluoromethyl)-2-quinolinyl]-2-propen-1-one), AZ26 (N-[p-(3-Cyano-1-isobutyl-1H-indol-5-yloxy)phenyl]-(S)-2- pyrrolidinecarboxamide), AZ67 (N-(p-{3-cyano-1-[(3,5-dimethyl-4- 10 isoxazolyl)methyl]-1H-indol-5-yloxy}phenyl)-(S)-2-pyrrolidinecarboxamide) or a salt thereof.

13. The method of any one of claims 1-12 wherein the pharmaceutically acceptable formulation is administered by intranasal, intrathecal, oral, or 15 parenteral route.

14. The method of claim 1 wherein the glycolysis inhibitor is administered for the prevention of a post-surgical pain, chemotherapy-induced or neuropathic pain. 20 15. Use of at least one glycolysis inhibitor in the manufacture of a medicament in a pharmaceutically acceptable formulation comprising the at least one glycolysis inhibitor according to any one of claims 1-12 and one or more pharmaceutically acceptable excipients.

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