Important Compound Classes
Title
Protein Tyrosine Phosphatase Inhibitors and Methods of Use Thereof
Patent Publication Number
WO 2021/127499 A1
Publication Date
June 24, 2021
Priority Application
US 62/949,613
Priority Date
December 18, 2019
Inventors
Farney, E. P.; Shiroodi, R. K.; Xiong, Z.; Zhang, Q.; O’connor, M.; Halvorsen, G. T.; Zhao, H.; Baumgartner, C.; Frost, J. M.; Kym, P. R.; Abbott, J. R.; Bogdan, A.; Economou, C.; Wang, X.
Assignee Company
Calico Life Sciences LLC; 1170 Veterans Blvd., South San Francisco, CA 94080 (USA). AbbVie Inc.; 1 North Waukegan Road, North Chicago, IL 60064 (USA).
Disease Area
Cancer and metabolic diseases
Biological Target
Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) and/or protein tyrosine phosphatase nonreceptor type 1 (PTPN1)
Summary
The invention in this patent application relates to 5-(naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide derivatives represented generally by formula 1. These compounds are inhibitors of PTPN2 and/or PTPN1 and may be useful for the treatment of cancer or metabolic diseases.
A main immune system function is the protection of the human body against the occurrence of malignancy by eliminating damaged, altered, or aged cells. The DNA in many mutated cancer cells produce abnormal proteins known as tumor antigens, which marks them as altered or damaged. The immune system is capable of surveillance and detection of cancer cells and then attack and destroy them on a regular basis under normal conditions. However, cancer cells seem to develop the ability of evading detection by the immune system and escape its response that ordinarily prevents the development of malignant tumors. There are several mechanisms by which the tumor cells can evade the effects of the immune system, including the selection of tumor variants resistant to immune effectors (known as immune editing) and progressive formation of an immune suppressive environment within the tumor.
Understanding how cancer cells evade the immune system response helped researchers to design a novel and potentially universal treatment for different kinds of cancer. This novel therapeutic approach, known as immunotherapy, can restore the immune system natural ability of identifying and destroying cancer cells by blocking the pathways used by cancer cells to evade the immune response. It can also work through introducing certain components to boost the ability of the immune system in detecting cancer cells. The concept of immunotherapy has been known since the late 19th century, and there were many unsuccessful attempts for its use over decades. Along the way, scientists have made many discoveries that helped them better understand immunotherapy but did not lead to a useful cancer treatment. It was not until the work of James Allison (United States) and Tasuku Honjo (Japan) in the late 1990s on blocking the immune checkpoints CTLA-4 and PD-1, respectively, that made this approach possible as a new promising cancer therapy. The two scientists were jointly awarded “The 2018 Nobel Prize in Physiology or Medicine” in recognition of their pioneering research to develop a clinically useful application of immunotherapy in cancer treatment after years of skepticism over the usefulness of this approach. Their work has also inspired the discovery and approval of several drugs such as the CTLA-4 blocker ipilimumab (Yervoy) in 2011 as well as the PD-1 blockers nivolumab (Opdivo) and pembrolizumab (Keytruda) in 2014.
Unlike traditional cancer treatments (chemotherapy and radiation) that attack both cancer and healthy cells, immunotherapy can specifically target cancer cells; therefore, it promises fewer adverse effects. However, immunotherapy is still limited to the treatment of only few cancers and does not work for all patients. Scientists are continuing their research to introduce novel strategies to expand its use and realize its full potential in cancer treatment. There are several promising approaches to treat cancer with immunotherapy including but not limited to the following:
Many cancer tumors survive by stimulating the immune checkpoints, which diminishes the immune system ability to response in attacking cancer cells. Blocking these checkpoints is an immune modulatory strategy that can restore the immune system ability to attack and kill cancer cells.
Specifically designed monoclonal antibodies may bind to and mark cancer cells to facilitate their recognition and destruction by the immune system.
The patient’s autologous T-cells can be genetically modified to express chimeric antigen receptor (CAR) specific for a tumor antigen to enhance the T-cells abilities to target and kill cancer cells. The enhanced CAR T-cells are grown by ex-vivo expansion and then reinfused into the patients’ blood to boost their immune response. The process is called CAR T-cell therapy or adoptive cell therapy.
Tumor cells can evade the immune response by stimulating the immune checkpoints to inhibit the activation and function of cytotoxic CD8+ T cells. The immune checkpoint receptors, such as the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 (PD-1), suppress the T-cell responses with the aid of phosphatases to reverse the kinase signaling activation induced by the T-cell receptor (TCR) and costimulatory receptors such as the cluster of differentiation 28 (CD28) on αβ T cells.
The approved immunotherapy drugs ipilimumab, nivolumab and pembrolizumab are monoclonal antibodies capable of blocking checkpoints such as CTLA-4 and PD-1/PD-L1 pathways. The use of these checkpoint blockers proved effective in treating a variety of cancers. However, they are still limited in scope due to incomplete clinical responses and the development of intrinsic or acquired resistance. Therefore, there remains a need for identifying improved clinical strategies to overcome these limitations and expand the use of this immunotherapy approach to effectively treat more kinds of cancer.
The protein tyrosine phosphatase (PTP) family functions to dephosphorylate the phosphorylated amino acid residues on proteins. The PTP family contains 107 known PTPs divided into four classes (I, II, III, and IV). Class I is the largest with 99 members, and it is further divided into two groups: 38 tyrosine-specific phosphatases and 61 dual-specificity phosphatases. They play critical roles in regulating essential cellular signaling functions, including cell proliferation, differentiation, and survival. Protein tyrosine phosphatase nonreceptor type 2 (PTPN2), also known as T cell protein tyrosine phosphatase (TC-PTP), is an intracellular member of class I subfamily of tyrosine-specific phosphatases. It is ubiquitously expressed, but its expression is highest in hematopoietic and placental cells. Human PTPN2 exists in two splice variants:
a 45 kDa principal form that contains a nuclear localization signal at the C-terminus upstream of the splice junction; it can passively transfuse into the cytosol under certain cellular stress conditions
a 48 kDa canonical form which has a C-terminal endoplasmic reticulum (ER) retention motif
The two PTPN2 isoforms share a phosphotyrosine phosphatase catalytic domain at the N-terminal.
PTPN2 negatively regulates the signaling of nonreceptor tyrosine kinases (e.g., JAKl and JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSFlR, and PDGFR), transcription factors [e.g., signal transducer and activator of transcription (STAT) factors such as STAT1, STAT3, and STAT5a/b], and Src family kinases (e.g., Fyn and Lek). In addition, PTPN2 is an essential negative regulator of the JAK-STAT pathway. In this role, it acts to directly regulate signaling through cytokine receptors, including interferon gamma (IFNγ).
The in vivo loss of function genetic screen using CRISPR/Cas9 genome editing in a mouse Bl6-F10 transplantable tumor model has revealed significant findings including the following:
Deletion of PTPN2 gene in tumor cells improved response to immunotherapy treatment with a GM-CSF secreting vaccine (GVAX) plus PD-1 checkpoint blockade
Loss of PTPN2 sensitizes tumors to immunotherapy by enhancing IFNγ-mediated effects on antigen presentation and growth suppression.
Under immunotherapy selective pressure, PD-L1 and cluster of differentiation 47 (CD47) genes, known to be involved in immune evasion, were depleted while genes involved in the IFNγ signaling pathway, including IFNGR, JAK1, and STAT1, were enriched.
These findings suggest that enhancing IFNγ sensing and signaling through the inhibition of PTPN2 is a potential therapeutic strategy to improve the efficacy of cancer immunotherapy regimens.
The PTPN2 catalytic domain shares 74% sequence homology and similar enzymatic kinetics with another family member, the protein tyrosine phosphatase nonreceptor type 1 (PTPN1) also known as protein tyrosine phosphatase-1B (PTP1B). Studies have determined a key role for PTPN1 in a primary mechanism for down-regulating both insulin and leptin receptor signaling pathways. Animal studies have determined that deficiency in PTPN1 has improved glucose regulation and lipid profiles. Animals deficient in PTPN1 are also resistant to weight gain even under a high fat diet. Thus, PTPN1 inhibitors are potentially useful for the treatment of type 2 diabetes, obesity, and metabolic syndrome.
The compounds of formula 1 disclosed in this patent application are inhibitors of the protein tyrosine phosphatase PTPN2 and/or PTPN1. The above data suggest that these compounds may provide effective therapy to treat cancer as well as type 2 diabetes, obesity, metabolic diseases, or any other disease, disorder or ailment favorably responsive to PTPN2 or PTP1B inhibitor treatment.
Key Structures
The inventors described the structures
and methods of synthesis for 291 examples of formula 1 (compound numbers
100 to 390) including the following representative examples:
Biological Assay
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1.
Mobility shift assay (MSA) used to determine potency of PTPN2 inhibitors
-
2.
Mobility shift assay (MSA) used to determine potency of PTP1B inhibitors
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3.
B16F10 IFNγ-induced cellular growth inhibition assay
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4.
T cell activation and function assays
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5.
In vivo efficacy of PTPN2 inhibitors in MC38 tumor model and impact on pharmacodynamic markers
Biological Data
The biological data obtained from testing the above representative examples in the first three assays are listed in the following two tables.
Recent Review Articles
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The author declares no competing financial interest.