WO2020152280A1 - Inhibiteurs de lsd1 destinés à être utilisés dans le traitement du diabète de type 2 - Google Patents

Inhibiteurs de lsd1 destinés à être utilisés dans le traitement du diabète de type 2 Download PDF

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WO2020152280A1
WO2020152280A1 PCT/EP2020/051654 EP2020051654W WO2020152280A1 WO 2020152280 A1 WO2020152280 A1 WO 2020152280A1 EP 2020051654 W EP2020051654 W EP 2020051654W WO 2020152280 A1 WO2020152280 A1 WO 2020152280A1
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lsd1
pancreatic
concentration level
cells
differentiation
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PCT/EP2020/051654
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English (en)
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Benoit Raymond Gauthier
Petra Isabel LORENZO OVEJERO
Esther DE LA FUENTE MARTÍN
Nadia COBO VUILLEUMIER
José Manuel MELLADO GIL
Francisco Javier BERMÚDEZ SILVA
Gemma ROJO MARTÍNEZ
José Carlos REYES ROSA
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Fundación Pública Andaluza Progreso Y Salud
Servicio Andaluz De Salud
Consejo Superior De Investigaciones Cientificas (Csic)
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Publication of WO2020152280A1 publication Critical patent/WO2020152280A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention refers to the medical field. Particularly, it is focused on the use of Lysine specific demethylase (LSD1) inhibitors for the treatment of type 2 diabetes, by means of the re-differentiation of pancreatic beta cells once they have been de-differentiated.
  • LSD1 Lysine specific demethylase
  • Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.
  • Type 2 diabetes primarily occurs as a result of obesity and lack of exercise. Some people are more genetically at risk than others. Type 2 diabetes makes up about 90% of cases of diabetes, with the other 10% due primarily to diabetes mellitus type 1 and gestational diabetes. In diabetes mellitus type 1 there is a lower total level of insulin to control blood glucose, due to an autoimmune induced loss of insulin-producing beta cells in the pancreas. Diagnosis of diabetes is by blood tests such as fasting plasma glucose, oral glucose tolerance test, or glycated hemoglobin (AIC).
  • AIC glycated hemoglobin
  • Type 2 diabetes is partly preventable by staying a normal weight, exercising regularly, and eating properly. Treatment involves exercise and dietary changes. If blood sugar levels are not adequately lowered, the medication metformin is typically recommended. Many people may eventually also require insulin injections. In that on insulin, routinely checking blood sugar levels is advised; however, this may not be needed in those taking pills. Bariatric surgery often improves diabetes in those who are obese. Rates of type 2 diabetes have increased markedly since 1960 in parallel with obesity. As of 2015 there were approximately 392 million people diagnosed with the disease compared to around 30 million in 1985. Typically it begins in middle or older age, although rates of type 2 diabetes are increasing in young people. Type 2 diabetes is associated with a ten-year- shorter life expectancy.
  • Loss of the fully differentiated phenotype is a recognized potential mechanism underlying loss of b-cell function in type 2 diabetes.
  • the metabolic stress of chronic nutrient oversupply can lead to reduced expression or nuclear activity of key b-cell transcription factors, including Pdxl, Nkx6.1, and MafA.
  • b-Cell dysfunction ensues from a combination of decreased insulin biosynthesis and loss of physiological nutrient-secretion coupling. This has been demonstrated in a number of models of glucotoxicity, including partial pancreatectomy, with changes largely prevented by maintenance of normoglycemia, and in b-cells in vitro after chronic palmitate exposure.
  • Re-differentiation provides an attractive potential underlying mechanism for recovery of b- cell function after a reduction in islet fat content over the time course observed in vivo in humans.
  • the dedifferentiated state could be considered as providing a“hideaway” until the metabolic insult subsides, offering an opportunity for restoration of the end-differentiated state after alleviation of metabolic stresses.
  • the potential for re-differentiation as a mechanism underlying restoration of b-cell function in type 2 diabetes is illustrated by the restoration of b-cell function by intensive insulin therapy in a rodent model of hyperglycemia.
  • This restoration in b-cell function was associated with b-cell re-differentiation characterized by increased levels of mature b-cell markers, including insulin, Pdxl, and MafA.
  • a small molecule inhibitor of the transforming growth factor-b receptor (Alk5) was shown to be capable of reversing b-cell dedifferentiation in islets isolated from mice with extreme diabetes, with urocortin 3 used as a marker for mature b-cells.
  • Potential translation to human disease was indicated by incubation of isolated human islets with ALK5 inhibitor, bringing about increased expression levels of a number of mature b-cell markers, including insulin, Pdxl, and MafA.
  • ALK5 inhibitor administered to diabetic animals failed to improve glycemic control and caused an overall deterioration in health. This highlights the requirement for development of pathway-specific therapeutics to restore mature, functional b-cells if a successful pharmacological approach to controlling type 2 diabetes is to be developed.
  • the present invention is focused on solving the above cited problem and provides a new strategy for the treatment of type 2 diabetes, by means of the re-differentiation of pancreatic b-cells, once they have been de-differentiated.
  • the present invention provides a new strategy for the treatment of type 2 diabetes, preferably by means of the re-differentiation of pancreatic b-cells, once they have been de-differentiated.
  • the first embodiment of the present invention refers to Lysine specific demethylase (LSD1) inhibitors for use in the treatment of type 2 diabetes.
  • the present invention refers to LSD1 inhibitors for use in the differentiation of pancreatic b-cells, particularly for the re-differentiation of pancreatic b-cells once they have been de-differentiated.
  • LSD1 inhibitors for use in the differentiation of pancreatic b-cells, particularly for the re-differentiation of pancreatic b-cells once they have been de-differentiated.
  • type 2 diabetes is treated in the present invention by means of the administration of LSD 1 inhibitors which are able to re-differentiate pancreatic b-cells once they have been de-differentiated.
  • the inhibitors used in the present invention are not only directed to the inhibition of the activity of LSD 1 but they are also directed to inhibit the expression of KDM1A gene which encodes the protein LSD1.
  • the re-differentiation of pancreatic b-cells and the treatment of type 2 diabetes can be achieved not only by inhibiting the activity of LSD 1 but also by inhibiting the expression of KDM1A gene.
  • the stimulation of HMG20A by any means known in the prior art, could directly give rise to the re-differentiation of pancreatic b-cells and the treatment of type 2 diabetes.
  • the stimulation of HMG20A inhibits the activity of LSD 1 and consequently, again, the stimulation of HMG20A could be directly used for re-differentiating pancreatic b-cells and treating type 2 diabetes.
  • LSD1 is defined in the present invention as a therapeutic target whose inhibition would result in improving the health of patients suffering from type 2 diabetes. Consequently, according to the present invention, any compound or molecule able to inhibit LSD1 and /or KDM1A can be used for re-differentiating pancreatic b-cells and treating type 2 diabetes.
  • said LSD1 inhibitors a compound of Formula I
  • the LSD1 inhibitor is the compound Trans-Nl-((lR,2S)-2- phenylcy cl opropyl)cyclohexane- 1,4-diamine (ORY-1001) (CAS Number: 1431304-21-0), characterized by Formula II:
  • the most important technical feature of the present invention is the inhibition of LSD1 and /or KDM1A for treating type 2 diabetes, irrespective of the molecule or compound which is used for reaching said inhibition.
  • compounds of Formula I preferably the compound of Formula II
  • any of compound or molecule able to inhibit LSD1 and /or KDM1A could be used according to the present invention for treating type 2 diabetes.
  • examples of LSD 1 inhibitors that can be used in the present invention are disclosed in the international patent applications W02010084160 and WO2012072713 which are herein incorporated by reference in its entirety.
  • each of Ri -R5 is independently chosen from -H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryl oxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, suifmy
  • A is cyclyl optionally having 1 , 2, 3 or 4 substituents A' .
  • said cyclyl is aryl or heteroaryl.
  • Said aryl is preferably phenyl.
  • Said heteroaryl is preferably selected from pyridinyl, pyrimidinyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, furanyl or thiazolyl, more preferably said heteroaryl is selected from pyridinyl, pyrimidinyl or thiazolyl, still more preferably said heteroaryl is pyridinyl (in particular, pyridin-2-yl or pyridin-3-yl) or thiazolyl (in particular thiazol-5-yl) and even more preferably said heteroaryl is pyridin-3-yl or thiazol- 5-yl.
  • said cyclyl (or said aryl or said heteroaryl, or any of the above- mentioned specific aryl or heteroaryl groups) is unsubstituted or has 1 or 2 substituents A', and it is more preferred that said cyclyl (or said aryl or said heteroaryl, or any of the above- mentioned specific aryl or heteroaryl groups) is unsubstituted or has 1 substituent A .
  • Said substituent(s) A' is/are each independently selected from -LI -cyclyl (e.g., -L'-aryl, -L' - cycloalkyl or -L'-heterocyclyl), alkyl, alkenyl, alkynyl, alkoxy, amino, amido (e.g., -CO- NH2), -CH2-CO-NH2, alkyl amino, hydro yl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfonyl, sulfmyl, sulfonamide, acyl, carboxyl, carbamate or urea, wherein the cyclyl moiety comprised in said -LI -cyclyl is optionally further substituted with one or more (e.g., 1 , 2 or 3) groups independently selected from halo, haloalkyl, haloalkoxy, aryl, aryl
  • the cyclyl moiety comprised in said -LI -cyclyl is unsubstituted or is substituted with one of the above groups (including, e.g., one of the preferred groups halo, haloalkyl, N-sulfonamido or cyano).
  • the cyclyl moiety comprised in said -L'-cyclyl is substituted with one of the above groups (including, e.g., one of the preferred groups halo, haloalkyl, N- sulfonamido or cyano).
  • the cyclyl moiety is unsubstituted.
  • Said -LI -cyclyl is preferably -L'-aryl, -L'-cycloalkyl or -L' -heterocyclyl (e.g., -LI - heteroaryl or -LI -heterocycloalkyl), more preferably -L ' -aryl or -LI -heteroaryl, even more preferably -L'-aryl, even more preferably -LI -phenyl.
  • Each LI is independently selected from a covalent bond, -(CH2) i -6-, -(CH2)0-3-0-(CH2)o-3-, -(CH2)o-3-NH-(CH2)o-3- or - (CH2)o-3-S-(CH2)o-3-, preferably from a covalent bond, -(CH2) i 3-, -0-(CH2)o-3- or -NH- (CH2)0-3-, more preferably from a covalent bond, -CH2-, -0-, -O-CH;-, -0-(CH2)2-, -NH- or -NH-CH2-, even more preferably from a covalent bond, -CH2- or -0-CH2-.
  • the aforementioned groups LI (connecting the moiety A to the cyclyl moiety comprised in -L'-cyclyl) are in the specific orientation indicated above (accordingly, the group "-0-CH2-" as an example for LI is preferably in the orientation ( ..)-A-0-CH2-cyclyl).
  • KDM1A/LSD1 inhibitors could be used in the present invention:
  • the LSD1 inhibitor is used for the re- differentiation of pancreatic b-cells once they have been de-differentiated, preferably for the treatment of type 2 diabetes.
  • the second embodiment of the present invention refers to a pharmaceutical composition comprising any of the LSD1 inhibitors described above, for use in the differentiation of pancreatic b-cells, preferably in the re-differentiation of pancreatic b-cells once they have been de-differentiated, more preferably in the treatment of type 2 diabetes.
  • the third embodiment of the present invention refers to LSD1 for use in the differentiation of pancreatic b-cells, preferably in the re-differentiation of pancreatic b-cells once they have been de-differentiated, more preferably in the treatment of type 2 diabetes, wherein LSD1 activity is inhibited by means of a LSD1 inhibitor.
  • the fourth embodiment of the present invention refers to an in vitro method for screening, identifying and/or producing LSD1 inhibitors suitable for the differentiation of pancreatic b- cells, for the for the re-differentiation of pancreatic b-cells once they have been de differentiated or for the treatment of type 2 diabetes which comprises: (a) Measuring at least the activity or the concentration level of LSD 1 in a biological sample isolated from the patient after the administration of the candidate compound; (b) wherein if the activity or the concentration level of LSD 1 determined in step (a) is statistically lower than the activity or concentration level of LSD1 determined before the administration of the candidate compound, this is indicative that the candidate compound is a LSD1 inhibitor suitable for the differentiation of pancreatic b-cells, for the re-differentiation of pancreatic b-cells once they have been de-differentiated or for the treatment of type 2 diabetes.
  • the fifth embodiment of the present invention refers to an in vitro method for monitoring the efficacy or response to LSD1 inhibitors in the treatment of type 2 diabetes, in the differentiation of pancreatic b-cells, or in the re-differentiation of pancreatic b-cells once they have been de-differentiated, which comprises: a) Measuring the concentration level of C- peptide after the administration of the LSD1 inhibitor, wherein if the concentration level of C-peptide after the administration of LSD1 inhibitors is statistically higher than the concentration level of C-peptide determined in non-treated patients suffering from type 2 diabetes, this is an indication that pancreatic b-cells are being differentiated and that type 2 diabetes is being effectively treated with LSD1 inhibitors.
  • the LSD1 inhibitor before measuring the levels of C-peptide in order to determine the efficacy or response to LSD1 inhibitors, it is determined whether the LSD1 inhibitor is actually inhibiting the activity or reducing the concentration level of LSD1. This can be done by measuring the activity or the concentration level of LSD 1 in a biological sample isolated from the patient after the administration of a LSD1 inhibitor; wherein if the activity or the concentration level of LSD1 after the administration of the LSD1 inhibitor is statistically lower than the activity or the concentration level of LSD1 determined before the administration of the LSD1 inhibitor, this an indication that the LSD1 inhibitor is actually inhibiting the activity or reducing the concentration level of LSD1.
  • the sixth embodiment of the present invention refers to the in vitro use of LSD1 for screening, identifying and/or producing LSD1 inhibitors suitable for the differentiation of pancreatic b-cells, preferably for the re-differentiation of pancreatic b-cells once they have been de-differentiated, more preferably for the treatment of type 2 diabetes.
  • the seventh embodiment of the present invention refers to the in vitro use of LSD1 for monitoring the efficacy of a treatment with LSD1 inhibitors in the differentiation of pancreatic b-cells, preferably in re-differentiation of pancreatic b-cells once they have been de-differentiated, more preferably in the treatment of type 2 diabetes.
  • the activity or concentration level before the treatment is used as a“reference” or“control level” for assessing whether the candidate compound is a LSD1 inhibitor suitable for the treatment of type 2 diabetes.
  • the concentration level of C-peptide in non-treated patients suffering from type 2 diabetes is used as a“reference” or“control level” for assessing whether the patient is responding to the treatment. If the concentration level of C-peptide determined after the treatment with LSD1 inhibitors is higher than the above cited “reference” or“control level”, this is an indication that the LSD1 inhibitor is properly working in the treatment of type 2 diabetes.
  • the activity or concentration level of LSD 1 before the treatment with LSD1 inhibitors is used as a“reference” or“control level” for assessing whether the LSD1 inhibitor is working properly. If the activity or concentration level of LSD1 determined after the treatment with LSD1 inhibitors is statistically lower than the above cited“reference” or“control level”, this is an indication that the LSD1 inhibitor is properly working in the inhibition of LSD 1.
  • ORY-1001 is not toxic for the insulinoma INS-1E cell line (insulin- secreting cell lines). Graphical representation of the total cell number in the different conditions used in the experiment, relative to the cell number in vehicle treated cells. Error bars represent standard deviation.
  • ORY-1001 treatment stimulates the expression of mature beta-cell markers in INS- 1E cell line (insulin-secreting cell lines). Graphical representation of the relative expression of the indicated genes referred to expression in vehicle treated cells. Expression levels were analysed by RT-PCR using specific primer pairs and corrected by the housekeeping gene beta-Actin.
  • Figure 3. ORY-lOOl treatment reverts the effect of HMG20A silencing in INS-1E cell line (insulin- secreting cell lines). Graphical representation of the relative expression of the indicated genes referred to expression in vehicle treated cells. Silencing of HMG20A induces a 50% decrease in the expression of HMG20A mRNA, correlating with a decrease in beta cells markers NeuroD, MafA and Insulin.
  • ORY-lOOl is not toxic for the insulinoma INS-1E cell line.
  • HMG20A is a chromatin binding factor, member of the High Mobility Group (HMG) box.
  • HMG High Mobility Group
  • GW AS studies have linked small nucleotide polymorphisms (SNPs) in the HMG20A gene to type 2 diabetes mellitus (T2DM) and gestational diabetes mellitus (GDM).
  • SNPs small nucleotide polymorphisms
  • T2DM type 2 diabetes mellitus
  • GDM gestational diabetes mellitus
  • HMG20A expression is transiently upregulated in mice during pregnancy, supporting the involvement of this factor in the adaptation process that takes place in islets during periods of increased insulin demand.
  • HMG20A silencing was analysed in the pancreatic cell line INS-1E, observing that the decrease in HMG20A expression correlates with the decrease in mature beta cell markers such as Insulin, MafA, and NeuroD, and increases the plasticity gene Pax4, suggesting that HMG20A is required for full maturation of beta cells.
  • HMG20A is a member of the LSD 1 -CoREST inhibitory complex.
  • HMG20A through the displacement of HMG20B from the complex, relieves the transcriptional repression imposed by the LSD 1 -CoREST. Therefore, the present invention suggests that the action of HMG20A in pancreatic islets is through its modulation of LSDl-CoREST complex.
  • LSD1- CoREST complex inhibition will potentiate the maturation of pancreatic beta cells. This premise was validated in the insulinoma cell line INS-1E.
  • ORY 1001 The toxicity of LSD1 inhibitor ORY 1001 was first analysed in this cell line. To do so, cells were incubated in the presence of increasing concentrations of ORY- 1001 for 24, 48 and 72h. At the end of the experiment total cell number was counted and represented relative to the cell number in vehicle treated cells after 72h in culture ( Figure 1). Total cell number after ORY-1001 treatment did not significantly change, indicating that ORY-1001 is not toxic for INS-1E cells at the concentrations and time points used.
  • ORY-1001 treatment stimulates the expression of mature beta-cell markers in INS-1E cell line.
  • the effect of ORY-1001 treatment on the expression of HMG20A-regulated genes was analysed. It was initially observed that HMG20A silencing induces a decrease in the expression of mature beta-cell markers such as NeuroD, MafA and insulin, and increased the expression of the transcription factors Pax4 and REST. Thus, the effect of ORY-1001 treatment onto the expression levels of these genes was analysed. Since for silencing experiments the cells were cultured for 72h after transfection, and in order to avoid any alteration due to the time in culture of the cells, INS-1E cells were cultured for 72h adding the inhibitor 6 and 16h before harvesting the cells.
  • transfected cells were treated with ORY-1001 50nM or vehicle.
  • silencing of HMG20A in vehicle treated cells induced the downregulation of the mature beta cell markers NeuroD, MafA and insulin.
  • ORY- 1001 reverted the effect of the downregulation of HMG20A, resulting in the increase of the expression of NeuroD, MafA and insulin.
  • All together these data indicates that the treatment of HMG20A depleted INS-1E cells with ORY-1001 restores the expression of mature beta cell markers, suggesting that the treatment of beta-cells with the LSD1 inhibitors ORY-1001 will likely enhance their maturation to functional beta-cells, being therefore a promising treatment for T2DM.

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Abstract

La présente invention est focalisée sur l'utilisation d'inhibiteurs de déméthylase spécifique de la lysine (LSD1) pour le traitement du diabète de type 2, au moyen de la re-différenciation des cellules bêta pancréatiques une fois qu'elles ont été dé-différenciées.
PCT/EP2020/051654 2019-01-24 2020-01-23 Inhibiteurs de lsd1 destinés à être utilisés dans le traitement du diabète de type 2 WO2020152280A1 (fr)

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Cited By (1)

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WO2022248506A1 (fr) * 2021-05-26 2022-12-01 Universite Paris-Saclay Détection de perte d'activité de kdm1a pour le diagnostic de troubles endocriniens

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Publication number Priority date Publication date Assignee Title
WO2022248506A1 (fr) * 2021-05-26 2022-12-01 Universite Paris-Saclay Détection de perte d'activité de kdm1a pour le diagnostic de troubles endocriniens

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