Invented by Kellen L. Olszewski, Ji-In Kim, Masha V. Poyurovsky, Kevin G. Liu, Anthony Barsotti, Koi Morris, Kadmon Corp LLC

The market for Glucose Uptake Inhibitors (GUIs) has been experiencing significant growth in recent years. GUIs are a class of drugs that target glucose uptake in cells, primarily in the treatment of diabetes and cancer. These inhibitors work by blocking the transporters responsible for glucose uptake, thereby reducing the amount of glucose available for cellular metabolism. The global prevalence of diabetes has been steadily increasing, with an estimated 463 million adults living with the disease in 2019. As a result, there is a growing demand for effective treatments that can help manage blood glucose levels. GUIs offer a promising solution by specifically targeting glucose uptake, which is a key factor in diabetes management. In addition to diabetes, GUIs have also shown potential in cancer treatment. Cancer cells have a high demand for glucose to fuel their rapid growth and proliferation. By inhibiting glucose uptake, GUIs can starve cancer cells of their energy source, potentially slowing down tumor growth and improving patient outcomes. The market for GUIs is primarily driven by the increasing prevalence of diabetes and cancer worldwide. Additionally, advancements in drug discovery and development have led to the identification of novel GUIs with improved efficacy and safety profiles. These factors have attracted the attention of pharmaceutical companies, leading to a surge in research and development activities in this field. Several GUIs have already been approved for clinical use, such as metformin, a widely prescribed drug for type 2 diabetes. However, there is still a significant unmet need for more effective and targeted GUIs. This has created opportunities for pharmaceutical companies to develop innovative drugs that can selectively inhibit glucose uptake in specific tissues or cell types. The market for GUIs is also expected to benefit from ongoing advancements in drug delivery technologies. Novel drug delivery systems, such as nanoparticles and liposomes, can enhance the bioavailability and targeted delivery of GUIs to specific tissues or cells. This can improve the therapeutic efficacy of these inhibitors while minimizing side effects. However, the market for GUIs is not without its challenges. The development of GUIs requires extensive research and clinical trials to demonstrate their safety and efficacy. Additionally, regulatory approvals and reimbursement policies can significantly impact the market dynamics. The high cost of drug development and the need for long-term clinical trials can also pose financial challenges for pharmaceutical companies. Despite these challenges, the market for GUIs is expected to continue growing in the coming years. The increasing prevalence of diabetes and cancer, coupled with advancements in drug discovery and delivery technologies, will drive the demand for effective GUIs. As more innovative inhibitors are developed and approved, patients will have access to better treatment options, improving their quality of life and overall health outcomes.

The Kadmon Corp LLC invention works as follows

Compounds that modulate glucose transport activity are provided herein and can be used to treat cancer, autoimmune disease, inflammation, infectious diseases and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and the known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments the compounds are of the formula I:nnwherein variables have values disclosed herein.

Background for Glucose Uptake Inhibitors

Glucose is a vital nutrient to many organisms. The control of glucose consumption and signaling is highly regulated. Many diseases are linked to defects in the regulation of glucose and may therefore be amenable to therapeutic intervention with glucose uptake inhibitors. “Glucose-uptake inhibitors are useful in many disease areas, including oncology and autoimmunity, inflammation and infection, viral diseases and metabolic disorders.

Compounds useful in the present invention include those with the formula I:”.

wherein:

The invention is at least partially based on the discovery, by scientists, of compounds that modulate glucose absorption activity. The compounds of the invention can be used to treat cancer in one embodiment. In another embodiment the compounds are used to treat autoimmune diseases. In a different embodiment, the compounds can be used to treat inflammation. In a different embodiment, the compounds can be used to treat infectious diseases. The compounds can be used to treat metabolic diseases in another embodiment. The compounds modulate glucose transport activity in certain embodiments by modulating cellular factors, such as those related to glycolysis, and known glucose transporters, like GLUT1 or other GLUT members.

DESCRIPTION DU DRAWINGS

FIG. “FIG. Cell Titer Glo from Promega was used to measure cellular ATP levels.

FIG. “FIG. 2A=UOK262, FIG. 2B=UOK269) were treated with the dose-curves of the compound from Example 136 (-?-), and the compound from Example 7 (-?-).. The IC50 as well as the LD50 are shown.

FIG. The dose-response graph for HT1080 cellular lines that have been treated with Example 31 (FIG. The dose-response curve for HT1080 cells treated (72 hours) with the compound of Example 31 (FIG. Example 7 (FIG.

FIG. The dose-response graph for HT1080 cellular treated with Example 31?/+10?M ABT737 (for 72 hours) is shown in Figure 4A-B. FIG. FIG. 4A displays relative cell numbers and IC50 values. FIG. “Figure 4B shows the cell death percentage (relatively to the number of cells plated).

FIG. The dose-response graph for HT1080 cells treated with Example 31?/+25?M H2O2 (72 hours). FIG. FIG. 5A displays IC50 values of the compound in Example 31?/+H2O2. FIG. FIG. 5B shows percentage of cell death after indicated treatments.

FIG. The dose response curve shown in 6A-B is for HT1080 cellular treated with ascorbic acid at the indicated concentrations (48 hours) of the compound from Example 31. FIG. FIG. 6A displays the IC50 of cell proliferation. FIG. FIG. 6B shows the LD50 of cell death.

FIG. “FIG. 7A-B” shows that Plasmodium Falciparum in culture is sensitive to glucose intake inhibition. FIG. 7A shows blood culture of P. falciparum HB3 strain (2% initial parasitemia, 1% hematocrit and O+ blood), which were seeded into 96-well plates and treated for 48 hours with varying concentrations the compound from Example 7 as well as chloroquine in 0.1%DMSO. The DNA was quantified using the standard Sybr Green I fluorescent assay. FIG. FIG. 7B shows cultures treated for 48 hours with different concentrations of compounds. The medium was harvested, and the extracellular lactic acids were quantified using LC-MS.

FIG. Compounds disclosed herein suppress the metabolism, function, and proliferation of activated cells. In FIG. In FIG. In FIG. In FIG. 8A, right pane, human CD4T cells were activated in the presence glucose uptake inhibitors for 48 hours. IL-17 secreted in the supernatant of the cells was measured using ELISA (R&D Systems). Cell Titer Glo from Promega was used to measure the proliferation. FIG. FIG.

FIG. The in vivo effectiveness of glucose uptake inhibitors is demonstrated in Figure 9 in a mouse model of experimental autoimmune brain encephalitis induced by Myelin Oligodendrocyte Glycoprotein. The compound from Example 7 (-?-), and the compound from Example 81( – — -) both delayed or reduced the end clinical scores (compared to vehicle control, -?-=vehicle).

Glucose is a vital nutrient to many organisms. The control of glucose consumption and signaling is highly regulated. Many diseases are caused by defects in the regulation of glucose and may therefore be amenable to treatment with glucose uptake inhibitors. “Glucose-uptake inhibitors are useful in many disease areas, including oncology and autoimmunity, inflammation and infection, viral diseases and metabolic disorders.

Reprogramming the cancer cell metabolism is one of the new hallmarks of cancer. Cancer cells use ‘aerobic glucoselysis’ to meet their energy needs for cell growth and division. Normal cells use a low-rate of glycolysis and then pyruvate is fully oxidized in the mitochondria. Cancer cells, however, rely on a high rate of glycolysis with lactic acid fermentation in the presence or oxygen. Because mitochondrial oxidation phosphorylation produces more ATP compared to glycolysis, cancer cells rely on higher rates of glucose consumption. Cancer cells often achieve this by up-regulating glucose transporters. Many well-characterized cancer genes are believed to increase both glycolytic enzymes as well as glucose transporters. The increased glucose consumption of most tumors is already being used in diagnostics. This cancer-wide phenomenon has led to the standard imaging technique of tumors using a radiolabelled glucose analog (18FDG). (Hanahan D., and R. A. Weinberg Hallmarks of Cancer: The Next Generation. Cell, 2011. 144(5): p. 646-74.) It is predicted that the inhibition of glucose uptake will affect cancer cells of a variety of tumor types, while having little impact on normal cells.

Annu Rev Immunol, 2013. Annu Rev Immunol, 2013. 31: p. 259-83.) Hyper-activation (e.g. As Th17,Th2, and Th1 play an important role in autoimmune diseases and inflammation, it would be expected that decreasing glycolysis rates in these cells will curb their release of inflammatory molecules. As inhibition of glucose uptake activates AMPK (a master regulator of regulatory T cells), it is also important to inhibit glucose uptake. J Immunol, 2011. J Immunol, 2011. The immune system is rebalanced by using glucose uptake inhibitors. Other immune cells (including macrophages and dendritic and B cells), as well as T cells, rely heavily upon glycolysis to develop, activate and perform their effector functions. It is therefore predicted that glucose-uptake inhibitors may be useful as immunesuppressants, and provide benefit in autoimmune and inflammation conditions.

Many infectious (viruses, parasites etc.) agents” The growth and expansion of many infectious agents (including viruses, parasites, etc.) is heavily dependent on glucose consumption. Therefore the use the glucose uptake inhibitors disclosed in this patent will be helpful for the prevention of infectious diseases. Plasmodia parasites, in particular, rely solely on glucose to produce energy. The parasites invade red blood cells, causing a massive increase in glucose transport modulated by the host cell’s GLUT1 transducers. After transporting glucose into red blood cells the parasites also need to transport glucose across their own cell membrane using additional parasite-encoded transporters, such as Plasmodium Falciparum Hexose Transporter 1 (PfHT1). The compounds described here are predicted to inhibit malaria by interfering with glucose transport at either stage. Many other infectious agents, including malaria, hijack mammalian cell machinery to support growth and often target host glucose metabolism. The activity of the glucose-transporter GLUT1 plays a critical role in the infection and replication HIV-1 within cultured T-cells (Loisel Meyer, S. et al. Glut1-mediated sugar transport regulates HIV). Proc Natl Acad Sci USA, 2012. 109(7): p. 2549-54). The induction of glucose uptake has also been noted in other viruses, such as the substantial increase in GLUT4 levels in human cytomegalovirus-infected fibroblasts (Yu, Y., T. G. Maguire, and J. C. Alwine, Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection. J Virol, 2011. 85(4): p. 1573-80). The use of glucose uptake inhibitors (that target parasite and/or host cellular components) disclosed in this application against these diseases is promising.

Hyperglycemia caused by diabetes can have a variety of long-term effects. In conditions where glucose is transported down a gradient, certain cells are dependent on passive glucose transporters. These cells will consume high levels of glucose. Inhibitors that block glucose uptake, in particular those that block GLUT1, could protect these cells from damage. The compounds disclosed herein, for example, may be useful in diabetic retinopathy. (Lu, L. et al. Suppression GLUT1: a new strategy to avoid diabetic complications. J Cell Physiol. 2013. J Cell Physiol, 2013. Clin Chim Acta (2015)).

Compounds useful in the present invention include those with the formula I:”.

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