Autotaxin (ATX) inhibitors for the treatment of pancreatic cancer

Abstract

1. An autotaxin (ATX) inhibitor or a pharma- ceutically acceptable salt thereof for use in a method for treating pancreatic cancer in a patient, optionally the method further comprising administering a TGF-β pathway inhibitor and / or an additional chemotherapeutic agent.

Description

[Technical field]

[0001] This application claims priority to GB2108245.8, filed June 9, 2021, the content and elements of which are incorporated herein by reference for all purposes.

[0002] The present invention relates to compounds, or pharma- ceutically acceptable salts thereof, for use in a method of treatment of pancreatic cancer, and combination methods comprising said compounds. [Background technology]

[0003] Pancreatic cancer is a malignant tumor of the pancreas. Early stage pancreatic cancer usually does not cause symptoms, so pancreatic cancer is called a "silent" disease. Therefore, it is difficult to detect pancreatic cancer in its early stages.

[0004] Pancreatic cancer is one of the most lethal cancers, with a very low 5-year survival rate of only 7%. Only 25% of pancreatic cancer patients are candidates for surgery at the time of diagnosis, and only about 20% of patients who undergo surgical resection survive for more than 5 years. Chemotherapy with gemcitabine is the standard of care, with a response rate of 5-10% and a median mean overall survival of 6 months (Burris et al. 1997).

[0005] Pancreatic ductal adenocarcinoma (PDAC), the most prevalent form of pancreatic cancer, is a growing health problem with increasing mortality worldwide, placing a significant economic burden on healthcare systems and severely impacting the quality of life of patients. In some regions, PDAC is predicted to become the second leading cause of cancer death. With the increasing incidence of pancreatic cancer in Western countries, there is a need for a better understanding of the risk factors and symptoms associated with this disease to inform both healthcare professionals and the general population about potential preventive and / or early detection measures. Currently, there is a lack of therapeutic approaches for early detection that would increase patient survival.

[0006] Pancreatic cancer progression is usually characterized by a significant stromal fibrotic response, including fibroblasts, immune cells, and dense extracellular matrix. The transforming growth factor-β (TGF-β) pathway is one of the signaling systems that has been identified as a major contributor to the development of this disease (Truty and Urrutia, 2007). Due to the highly fibrotic tumor microenvironment, traditional chemotherapy and radiotherapy have only moderate antitumor activity in pancreatic tumors. Similarly, immunotherapies such as α-PD-1 therapy, which are highly effective in other types of cancer, have been shown to be ineffective in pancreatic cancer. Therefore, new treatments for pancreatic cancer are desperately needed.

[0007] There is now growing evidence supporting the physiological role of lysophosphatidic acid (LPA) in regulating pancreatic cancer initiation, progression, and metastasis (Chen et al. 2021). LPA is a bioactive phospholipid that engages at least six receptors, LPAR1-6, each of which is coupled to a distinct G protein involved in various cellular activities, such as cell migration, proliferation, and differentiation. LPA is present in various body fluids, and LPA levels in plasma have been well characterized in terms of its role in blood clotting.

[0008] LPA is generated from lysophosphatidylcholine (LPC) by the extracellular lyso-PLD autotaxin (ATX), also called ectonucleotide pyrophosphatase / phosphodiesterase 2 (ENPP2). Increased ATX expression has been reported in multiple cancers, including pancreatic cancer. Overexpression of both ATX and LPA in pancreatic tissues has been reported in pancreatic cancer patients, and thus the ATX-LPA axis may represent a potential target in pancreatic cancer.

[0009] There is a growing demand for targeted therapies in the treatment of pancreatic cancer. Targeted therapies are directed at specific receptors or enzymes present in tumors and, unlike traditional treatments such as chemotherapy, do not harm healthy tissue. Summary of the Invention

[0010] The present invention relates to a compound for use in the treatment of pancreatic cancer.The compound is an ATX inhibitor.The inventors have recognized that ATX inhibitors may be useful in targeted therapy for the treatment of pancreatic cancer.

[0011] In a first aspect, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof. The compound of formula I may be referred to herein as "Compound 1."

[0012] The term pancreatic cancer includes any type of exocrine or neuroendocrine pancreatic cancer. In some cases, pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC is the most common neoplastic disease of the pancreas, accounting for more than 90% of all pancreatic malignancies.

[0013] Suitably, Compound 1 is administered in a pharmaceutical composition comprising Compound 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent, carrier or excipient. Preferably, but not necessarily, the pharmaceutical composition is suitable for oral administration.

[0014] In some cases, the treatment is a combination therapy and includes one or more additional chemotherapeutic agents and / or TGF-β pathway inhibitors. The inventors have observed that administering Compound 1 together with an approved chemotherapeutic agent improves tumor growth inhibition and reduces side effects observed with the chemotherapeutic agent alone.

[0015] For example, the method may include administering a therapeutically effective amount of an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents. Suitable chemotherapeutic agents include gemcitabine and nab-paclitaxel. Thus, the method of the present invention may include administering gemcitabine and / or nab-paclitaxel.

[0016] The present inventors have observed that when TGF-β pathway inhibitors are administered, the therapeutic outcome is improved, particularly in terms of patient survival. Suitable TGF-β pathway inhibitors may include galunisertib, bactosertib, LY3200882, and AVID200.

[0017] Thus, in some cases, the method includes administering a therapeutically effective amount of a TGF-β pathway inhibitor, such as galunisertib. In some cases, the method includes a triple therapy of compound 1 or a pharmaceutically acceptable salt thereof, a TGF-β pathway inhibitor, and an additional chemotherapeutic agent, optionally two additional chemotherapeutic agents. In some cases, the triple therapy is compound 1 or a pharmaceutically acceptable salt thereof, galunisertib, and gemcitabine.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS Embodiments and experiments illustrating the principles of the present invention will now be described with reference to the accompanying drawings. [Brief description of the drawings]

[0019] [Figure 1] 1 shows the expression of ATX in pancreatic cancer samples compared to healthy tissue. [Diagram 2] 1 shows the anti-tumor growth activity of Compound 1 in the mPA6115-luc (MuPrime) mouse model. [Diagram 3] 1 shows the activity of Compound 1 in a Panc-1 mouse xenograft model. [Figure 4] 1 shows the activity of Compound 1 plus gemcitabine in the orthotopic Panc-1 mouse model. [Diagram 5] 1 shows the activity of Compound 1 plus gemcitabine and / or galunisertib in the RC416 orthotopic mouse model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Aspects and embodiments of the invention are described herein. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference.

[0021] compound 1 WO2016124939 describes various ATX inhibitor compounds, including compound 1, and their use in the treatment of proliferative diseases in which ATX activity is implicated.

[0022] Compound 1 is Example 40 of WO2016124939, which is incorporated herein by reference in its entirety. WO2016124939 lists over 200 examples. The structure of Compound 1 is according to Formula I: [ka]

[0023] Its IUPAC name is N-[(S)-1-(4-chloro-phenyl)-ethyl]-3-[3-(4-trifluoromethoxy-benzyl)-3H-imidazo[4,5-b]pyridin-2-yl]-propionamide. Its synthesis and characterization are described in WO2016124939, pages 77 and 82, respectively, the information of which is expressly incorporated herein by reference.

[0024] Compound 1 can be provided as a free base or as a pharma- ceutically acceptable salt. In some cases, Compound 1 is provided and administered as a free base.

[0025] formulation Preferably, compound 1 is provided as a pharmaceutical composition formulated for oral administration. This pharmaceutical composition may be provided in capsule or tablet. In some cases, it is provided in tablet. In other cases, it is provided as a powder or granular composition, or a liquid composition in capsule, for example, hard or soft shell capsule, for example, hydroxymethylcellulose (HPMC) capsule. In other words, oral dosage form is preferred.

[0026] The formulation suitably comprises one or more pharma- ceutically acceptable fillers, disintegrants, glidants, and / or lubricants.

[0027] Treatment of pancreatic cancer with compound 1 Compound 1 is an ATX inhibitor, which acts extracellularly and stimulates cancer proliferation, survival, and metastasis at multiple levels, making it an attractive target for the treatment of pancreatic cancer.

[0028] It is recognized in the art that LPA-ATX pathway is frequently activated in pancreatic cancer.Therefore, the method of the present invention can be related to the treatment of pancreatic cancer characterized by the upregulation of ATX-LPA pathway.Therefore, the method of the present invention can be related to the treatment of pancreatic cancer by regulating the ATX-LPA pathway of patients.

[0029] Pancreatic cancer can include any type of exocrine or neuroendocrine pancreatic cancer.Accordingly, the method of the present invention is directed to the treatment of pancreatic cancer, including, but not limited to, pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET or PNET).In some cases, pancreatic cancer is pancreatic ductal adenocarcinoma.In some cases, pancreatic cancer is pancreatic neuroendocrine tumor.

[0030] Methods of the Invention As described in more detail below, the present inventors have surprisingly found that compound 1 exhibits strong antitumor activity and is well tolerated in preclinical models of pancreatic cancer. Thus, it is possible to provide an ATX inhibitor that has antitumor activity and a good safety profile in pancreatic cancer.

[0031] Furthermore, the present inventors have surprisingly found that compound 1 increases the antitumor activity of standard chemotherapy such as gemcitabine. Therefore, an ATX inhibitor that can enhance the efficacy of chemotherapy in pancreatic cancer can be provided.

[0032] Thus, in some cases, the methods of the present invention are directed to combination therapy, which includes treatment of a patient with Compound 1, or a pharma- ceutically acceptable salt thereof, and an additional chemotherapeutic agent, such as gemcitabine (Gemzar®) or nab-paclitaxel (Abraxane®).

[0033] It will be understood that compound 1 and additional chemotherapeutic agent can be suitably administered at different times and / or different schedules, and can be formulated for administration by different routes, although not necessarily.For example, compound 1 or its pharmaceutically acceptable salt can be given as an oral dose, for example, a daily oral dose, while additional chemotherapeutic agent can be given as an infusion.For example, both gemcitabine and nab-paclitaxel can be administered on days 1, 8, and 15 of a 28-day cycle.

[0034] In some cases, the combination therapy includes treating the patient with Compound 1 or a pharma- ceutically acceptable salt thereof, gemcitabine, and nab-paclitaxel.

[0035] Furthermore, the inventors have found that the triple combination of Compound 1, galunisertib (a TGF-β pathway inhibitor) and chemotherapy shows further improved outcome in preclinical pancreatic cancer models.In some cases, the method includes administering a TGF-β pathway inhibitor.Suitable TGF-β pathway inhibitors can include galunisertib, bactosertib, LY3200882 and AVID200.

[0036] Thus, in some cases, the methods of the present invention are directed to combination therapy, which includes treatment of a patient with Compound 1 or a pharma- ceutical acceptable salt thereof, a TGF-β pathway inhibitor, such as galunisertib (LY2157299 monohydrate, Eli Lilley), and an additional chemotherapeutic agent, such as, for example, gemcitabine and / or nab-paclitaxel (Abraxane®).

[0037] It will be appreciated that Compound 1 and the TGF-β pathway inhibitor may suitably, but not necessarily, be administered at different times and / or on different schedules and may be formulated for administration by different routes.

[0038] Thus, the inventors have surprisingly found that pancreatic cancer can be treated with compound 1 with or without chemotherapy and with or without a TGF-β pathway inhibitor, and that the treatment is well tolerated, providing new monotherapy and combination therapy options for the treatment of pancreatic cancer.

[0039] The dose of Compound 1 can be provided once a day (QD), preferably twice a day (BID), and is preferably, but not necessarily, administered orally. Other methods of administration may be used. A suitable daily dose may be 5 mg to 2 g, for example 10 mg to 1 g. In some cases, when Compound 1 is administered in combination therapy, administration of Compound 1 is continued during the break in administration of the other agent (e.g., days 21 to 28 of a 28-day chemotherapy cycle). ***

[0040] The features disclosed in the foregoing description, or in the following claims, or in the accompanying drawings, and presented in a particular form or in terms of means for performing a disclosed function, or a method or process for achieving a disclosed result, may be used separately or in any combination of such features, as appropriate, to realize the invention in its diverse forms.

[0041] Although the present invention has been described in conjunction with the above exemplary embodiments, many equivalent modifications and variations will be apparent to those skilled in the art given this disclosure. Accordingly, the above exemplary embodiments of the present invention are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the spirit and scope of the present invention.

[0042] For the avoidance of doubt, the theoretical explanations provided herein are provided for the purpose of enhancing the understanding of the reader, and the inventors do not wish to be bound by any of these theoretical explanations.

[0043] Any section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0044] Throughout this specification, including the claims which follow, unless the context specifically requires, the words "comprise" and "include", as well as variations such as "comprises", "comprising" and "including", are understood to imply the inclusion of stated elements or steps, or groups of elements or steps, but not the exclusion of other elements or steps, or groups of elements or steps.

[0045] It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. The term "about" in connection with numerical values ​​is arbitrary and may mean, for example, + / - 10%. EXAMPLES

[0046] Example 1 ATX (ENPP2) expression in pancreatic cancer The expression of ENPP2 (the gene encoding autotaxin) in human pancreatic cancer samples was compared to normal pancreatic tissue using TCGA (cancer tissue) and GTEX (normal tissue) data. ENPP2 expression in tumor samples was found to be 1.85-fold higher than in normal tissue (see Figure 1 and Table 1). [Table 1]

[0047] Example 2 Activity of Compound 1 in the Orthotopic mPA6115-luc Mouse Model The therapeutic efficacy of compound 1 was evaluated in an orthotopic mPA6115-luc mouse model of pancreatic cancer. This model consists of transplantation of mPA6115-luc cells derived from spontaneously arising donor tumors in KPC mice into the pancreas of female wild-type C57BL / 6 recipient mice. The pathology and tumor microenvironment of this model closely resemble human pancreatic cancer and are characterized by limited immune cell infiltration.

[0048] The subcapsular region of the pancreas of each mouse was inoculated with mPA6115-luc tumor cells (1 × 10 6 The day of tumor cell inoculation is indicated as day 0.

[0049] Randomization is based on total flux (p / s, minimum flux > 1E 6 ) was initiated 4 days after tumor cell inoculation. Ten mice per group were assigned to treatment with vehicle (1% methylcellulose) or compound 1 (10 mg / kg in 1% methylcellulose) by BID oral gavage. Tumor growth and metastasis were imaged twice weekly by bioluminescence imaging.

[0050] As can be seen in FIG. 2, treatment of mPA6115-luc tumor-bearing mice with Compound 1 demonstrated a significant reduction in tumor growth based on total bioluminescence.

[0051] Example 3 Activity of Compound 1 in the xenograft PANC-1 mouse model The therapeutic efficacy of Compound 1 was evaluated in a subcutaneous PANC-1 mouse model of pancreatic cancer.

[0052] PANC-1 tumor cells (5 × 10 6 ) was inoculated subcutaneously. The day of tumor cell inoculation is indicated as day 0. Average tumor size >100 mm 3 Randomization began at time point 0.1. Ten mice were enrolled per study group. Tumor growth and body weight were measured twice weekly.

[0053] As can be seen in FIG. 3, treatment of PANC-1 tumor-bearing mice with Compound 1 demonstrated a reduction in tumor growth.

[0054] Example 4 Activity of Compound 1 Plus Gemcitabine in the Orthotopic PANC-1 Mouse Model The therapeutic effect of compound 1 with or without gemcitabine was evaluated in the orthotopic PANC-1 mouse model of pancreatic cancer, which consists of implantation of PANC-1 tumor cells into the pancreatic tissue of BALB / C nude mice.

[0055] PANC-1 tumor cells (3 × 10 ) in 50 uL of PBS containing Matrigel (1:1) were placed in the subcapsular region of the pancreas of each mouse. 6 ) were inoculated. The day of tumor cell inoculation was designated as day 0. Randomization began 10 days after tumor cell inoculation based on body weight. 10 mice per group were assigned to treatment with vehicle (1% methylcellulose, BID), gemcitabine (25 mg / kg, Q4D), compound 1 (10 mg / kg, BID), or compound 1 (10 mg / kg, BID) and gemcitabine (25 mg / kg, Q4D) by oral gavage. Tumor size was measured by weight at the end of day 42.

[0056] As shown in Figure 4, treatment of PANC-1 tumor-bearing mice with gemcitabine alone showed 41% tumor growth inhibition, but the treatment was poorly tolerated and 5 mice died or were sacrificed to reach a humane endpoint. Treatment with compound 1 alone resulted in a moderate tumor growth inhibition of 5%, while the combination of compound 1 and gemcitabine not only improved tumor growth inhibition to 47%, but also reduced the number of mice that died from gemcitabine treatment to only 2. See also Table 2. [Table 2]

[0057] Example 5 Activity of Compound 1 Plus Gemcitabine and / or Galunisertib in the Orthotopic RC416 Mouse Model The therapeutic efficacy of compound 1 with or without gemcitabine and / or galunisertib was evaluated in an orthotopic RC416 mouse model of pancreatic cancer. This model consists of transplanting RC416 cells derived from a spontaneously arising donor tumor in KPC mice into the pancreas of female wild-type C57BL / 6 recipient mice. The pathology and tumor microenvironment of this model closely resemble human pancreatic cancer and are characterized by high circulating ATX and TGF-β.

[0058] Each mouse was inoculated with RC416 tumor cells in the subcapsular region of the pancreas. The day of tumor cell inoculation was designated as day 0. Randomization was initiated 7 days after tumor cell inoculation based on body weight. Five mice per group were treated with vehicle (1% methylcellulose, orally twice daily), compound 1 (10 mg / kg, orally twice daily), galunisertib (50 mg / kg, orally twice daily), gemcitabine (75 mg / kg, intraperitoneally weekly), or a combination of compound 1 plus gemcitabine, compound 1 plus galunisertib and gemcitabine, and galunisertib plus gemcitabine for up to 28 days, and antitumor activity was measured by survival rate.

[0059] The results, shown in Figure 5, indicate that treatment with gemcitabine alone provided limited survival benefit. However, strikingly, the combination of gemcitabine with either compound 1 or galunisertib nearly doubled survival. Even more strikingly, combining all three treatments resulted in two mice surviving for over 65 days, further improving overall survival.

[0060] References A number of publications have been cited above in order to more fully describe and disclose the present invention and the state of the art to which it pertains. Full citations for these references are provided below. Each of these references is incorporated herein in its entirety. WO2016124939 Burris, HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15, 2403-2413 (1997). Chen, J., Li, H., Xu, W. & Guo, X. Evaluation of serum ATX and LPA as potential diagnostic biomarkers in patients with pancreatic cancer.Bmc Gastroenterol 21,58(2021). Truty, MJ & Urrutia, R. Basics of TGF-β and Pancreatic Cancer. Pancreatology 7, 423-435 (2007).

Claims

1. A compound of formula I for use in a method of treating pancreatic cancer in a patient: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. The compound or salt for use according to claim 1, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC).

3. The compound or salt for use according to claim 1 or 2, wherein the compound of formula I is administered in a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent, carrier or excipient, and the pharmaceutical composition is suitable for oral administration.

4. The compound or salt for use according to claim 1 or 2, wherein the method comprises administering a therapeutically effective amount of an additional chemotherapeutic agent.

5. The compound or salt for use according to claim 4, wherein the additional chemotherapeutic agent is gemcitabine.

6. The compound or salt for use according to claim 4, wherein the additional chemotherapeutic agent is nab-paclitaxel.

7. The compound or salt for use according to claim 4, wherein two additional chemotherapeutic agents are used.

8. The compound or salt for use according to claim 7, wherein the two additional chemotherapeutic agents are gemcitabine and nab-paclitaxel.

9. The compound or salt for use according to claim 1 or 2, wherein the method comprises administering a therapeutically effective amount of a TGF-β pathway inhibitor.

10. The compound or salt for use according to claim 9, wherein the TGF-β pathway inhibitor is selected from galunisertib, bracteosatib, LY3200882 and AVID200.

11. The compound or salt for use according to claim 9, wherein the TGF-β pathway inhibitor is galunisertib.

Images