BACKGROUND

IL-6 is an important cytokine that contributes to host defense against pathogens and IL-6/STAT3 signaling pathway plays a central role in regulating T effector/T regulatory (Teff/Treg) balance (1, 2). Teff/Treg balance is critical for the normal function of the immune system and impaired balance leads to either autoimmunity or increased susceptibility to foreign pathogens. IL-6/STAT3 pathway has recently been identified as the key cytokine-signaling pathway regulating Teff/Treg balance. First, IL-6, signaling through STAT3, induces the development of highly encephalitogenic myelin-specific Th17 cells. IL-6 differentiates naïve CD4 T cells into IL-17 producing Th17 cells, transferring severe disease in the experimental autoimmune encephalomyelitis (EAE) model of MS (3), (4, 5). Furthermore, IL-23, the cytokine crucial for the expansion of encephalitogenic myelin-specific Th17 cells in vivo and is required for EAE development (6-11), signals through STAT3 (12-15).

Thus, STAT3 is a common transcription factor regulating the development of encephalitogenic myelin-specific CD4 T cells by transducing signals from two inflammatory cytokines, IL-6 and IL-23 (FIG. 2). Via a positive feedback loop, IL-6 enhances expression and/or activation of IL-6 itself, IL-17 and STAT3 and vise versa (16, 17). Meanwhile, IL-6/STAT3 pathway is also a keysignaling pathway blocking the development of inducible T regulatory cells (iTreg), which is critical for dampening pathogenic inflammatory T effector responses. IL-6, signaling through STAT3, completely abrogates the de novo induction of iTreg cells (18, 19). As a result, dysregulated IL-6/STAT3 signaling skews Teff/Treg balance toward an enhanced T effector response, favoring the development of autoimmunity. In addition, IL-6/STAT3 signaling contributes to the resistance of Teff cells to Treg-mediated suppression (20, 21), which further impairs Teff/Treg balance, leading to increased susceptibility to autoimmunity.

Dysregulation of IL-6 signaling plays a significant role in the pathogenesis of MS and other autoimmune disease. IL-6 message and protein levels were elevated in the central nervous system (CNS) of MS patients (22, 23) and B cells from MS patients secret significantly more IL-6 than healthy controls (HC) (24). Furthermore, CD4 T cells from MS patients have significantly more IL-6 receptors (IL-6R) than HC (25) and the expression of phosphorylated STAT3 (pSTAT3) in peripheral blood mononuclear cells (PBMC) from relapsing-remitting MS (RRMS) patients strongly correlates with MS disease activity (26). T effector cells from active RRMS patients, but not HC, are resistant to Treg suppression and impaired Treg suppression correlates with an increase expression of IL-6R□ and pSTAT3. When STAT3 phosphorylation was blocked, the impaired suppression was reversed (20). All these data demonstrated a dysregulated IL-6/STAT3 signaling pathway in MS patients. Thus, IL-6/STAT3 signaling pathway may serve as an innovative target for reversing pathogenesis in MS patients. In support of this strategy, IL-6−/−, IL-23−/− and STAT3−/− mice are all completely resistant to EAE induction (10, 27-31), while injection of recombinant IL-6 induces severe EAE in IL-6-/− mice (28).

Moreover, constitutive activation of STAT3 has been found in a wide variety of cancers, including breast cancer, sarcomas, and other cancers, promoting it as a very attractive therapeutic target. Cytokines, hormones, and growth factors binding to the cell surface receptors can activate the JAK-STAT signaling pathway. The receptors are activated and phosphorylated by JAK kinase(s). Subsequently, the STAT3 monomer is phosphorylated at Tyrosine705 (pTyr705) by the same kinases through its SH2 domain binding to pY loop of the activated receptors, leading to STAT3 homodimer through its SH2 dimerization. The dimerized STAT3 then translocates into the nucleus and binds to DNA, turning on a host of oncogenes. Altogether, these events such as cell proliferation and apoptosis resistance.

Despite advances in developing therapeutic intervention targeting function of the IL6/STAT3 signalling pathway, there is still a scarcity of compounds that are both potent, efficacious, and safe inhibitors of IL6/STAT3 dysregulation during disease states and pathogenesis. These needs and other needs are satisfied by the present disclosure.

SUMMARY

In accordance with the purpose(s) of the disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to prodrug compositions of a STAT inhibitor compound. In some aspects, the STAT is STAT3. Disclosed are pharmaceutical compositions comprising the prodrug inhibitors of STAT. In various aspects, the prodrug inhibitors of STAT can be used in methods of treating an inflammatory disorder, including multiple sclerosis, or a disorder of uncontrolled cellular proliferation, such as a cancer.

Disclosed are compounds having a structure represented by a formula:


wherein each of R1and R2is independently selected from hydrogen and C1-C6 alkyl; wherein each of R3, R4, R5, R7, R8, and R9is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, —NO2, —NH2, and —OH; and wherein R20is —C(O)—O—(C1-C6 alkylene), —C(O)—(C1-C6 alkylene), —C(O)—(C1-C6 alkylene)—C(O)OH, —C(O)—NR21R22, and —(C1-C6 alkylene)—PO3H2; wherein each of R21and R22is independently selected from hydrogen and C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt, thereof, and a pharmaceutically acceptable carrier.

Also disclosed are methods for the treatment of an inflammatory disorder in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, thereof, or a disclosed pharmaceutical composition.

Also disclosed are methods for the treatment of a disorder of uncontrolled cellular proliferation in a mammal comprising the step of administering to the mammal administering a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, thereof, or a disclosed pharmaceutical composition.

Also disclosed are methods for inhibiting STAT activity in a mammal comprising the step of administering to the mammal administering a therapeutically effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, thereof, or a disclosed pharmaceutical composition.

Also disclosed are methods for inhibiting STAT activity in at least one cell, comprising the step of contacting the at least one cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt, thereof, or a disclosed pharmaceutical composition.

Also disclosed are kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt, thereof, or a disclosed pharmaceutical composition; and one or more of: at least one agent known to increase STAT activity; at least one agent known to decrease STAT activity; at least one agent known to treat a inflammatory disorder; at least one agent known to treat a disease of uncontrolled cellular proliferation; instructions for treating a disorder associated with a STAT dysfunction; instructions for treating an inflammatory disorder; or instructions for treating a disease of uncontrolled cellular proliferation.

Also disclosed are uses of a disclosed compound, a disclosed product of making, or a pharmaceutically acceptable salt thereof.

Also disclosed are uses of a disclosed compound, a disclosed product of making, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a STAT dysfunction in a mammal.

Also disclosed are methods for the manufacture of a medicament to inhibit a STAT protein in a mammal comprising combining at least one disclosed compound, a disclosed product of making, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or diluent.

While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

