Abstract
The invention in this patent application relates to 1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one derivatives represented generally by formula 1. These compounds are inhibitors of the E3 ubiquitin ligase, casitas B-lineage lymphoma proto-oncogene-b (CBL-B), and may be useful for the treatment of immunosuppression-associated diseases and disorders such as cancer and chronic viral infections.
Important Compound Classes
Title
Substituted Bicyclic Pyridone Derivatives
Patent Publication Number
WO 2024/105563 A1
URL: https://patents.google.com/patent/WO2024105563A1/en?oq=WO+2024105563+A1
Publication Date
May 23, 2024
Priority Applications
US 63/384,004; US 63/500,739; US 63/593,247
Priority Dates
November 16, 2022; May 8, 2023; October 26, 2023
Inventors
Bock, W. J.; Cho-Schultz, S.; Deal, J. G.; Donaldson, J. S.; Jalaie, M.; Jeffreys, M. S.; Kaiser, S. E.; Kath, J. C.; Montgomery, T. P.; Nair, S. K.; Patman, R. L.; Tran, K. T.; Wisniewska, H. M.; Zhou, R.
Assignee Company
Pfizer Inc., 66 Hudson Boulevard East, New York, New York 10001-2192, USA
Disease Area
Immunosuppression-associated diseases and disorders such as cancer and chronic viral infections
Biological Target
E3 ubiquitin ligase, casitas B-lineage lymphoma proto-oncogene-b (CBL-B)
Summary
Ubiquitin (Ub) is a 76-amino-acid protein that plays a very essential role in the modifications and regulation of the functions of many proteins through a process known as ubiquitylation (or ubiquitination). Ubiquitylation involves the binding of Ub to protein substrates and performing a three-step modification process with the aid of three classes of enzymes: Ub-activating enzymes (E1), Ub-conjugating enzymes (E2) and Ub ligases (E3).
The highly conserved casitas B-lineage lymphoma (CBL) family of proteins are ubiquitin E3 ligases. The family includes three homologues: CBL-B, c-CBL and CBL-3. These proteins share a highly conserved N-terminal region, which contains a RING (Really Interesting New Gene) finger (RF) domain, a short helical linker (L) domain and a tyrosine kinase-binding (TKB) domain. All three homologues of the CBL family play essential roles in the regulation of T cell functions and T cell immune tolerance. Immune tolerance is a negative regulation mechanism that causes immune cells to be unresponsive to self-antigens to prevent damage to healthy tissues.
The E3 ubiquitin ligase CBL-B is expressed primarily in dendritic cells (DCs), T cells and B cells of the immune system. It was originally characterized as a proto-oncogene. However, it was later identified as a key negative regulator of the T cell receptor (TCR). CBL-B establishes an activation threshold that prevents excessive activation of T cells and modulates the tolerance of peripheral T cells. Thus, it acts as a checkpoint regulator that maintains a balance between immunity and tolerance. CBL-B also regulates the related signal transduction in DCs, mast cells, and natural killer (NK) cells. In addition, CBL-B acts as a positive regulator of signal transduction in the tumor necrosis factor (TNF) receptor superfamily, members of which play key roles in innate and adaptive immune systems.
CBL-B knockout mice stimulated by antigen receptor and CD28 respond to stimulations by increasing the activity of T cells. This response promotes spontaneous autoimmunity and could lead to undesirable effects. On the other hand, it was observed that genetic loss or blocking of the CBL-B activity in syngeneic mouse tumor models caused enhanced innate and adaptive antitumor immunity. This effect leads to spontaneous tumor clearance that is believed to be mediated by CD8+ T cells. Thus, while the genetic ablation of CBL-B E3 ligase in mice promotes autoimmunity, it also improves tumor immune surveillance.
These and other studies using CBL-B-deficient mice suggest that the inhibition of CBL-B may potentially be a viable and beneficial therapeutic target to enhance antitumor immune response in various tumors and improve response to immunotherapy. However, based on the above findings, inhibition of CBL-B may also promote autoimmunity and can lead to inflammation and other undesirable adverse effects. Therefore, favorable CBL-B inhibitors can maintain enhanced antitumor activity and diminished undesirable autoimmune effects.
Selectivity of CBL-B inhibition is another factor to consider. The two CBL family homologues, CBL-B and c-CBL, share very similar structures but differ in their physiological functions and immune cell signal transduction. Studies have shown that simultaneous inhibition of these two closely related E3 ligase homologues is associated with possible increased adverse autoimmune risks. For example, mice containing T cells deficient in both CBL-B and c-CBL demonstrated a hypersensitive immune activation phenotype that develops lethal autoimmunity within 12–14 weeks after birth. Also, mice with global loss of both CBL-B and c-CBL develop systemic myeloproliferative disorder (a disorder that causes overproduction of red blood cells, white blood cells or platelets) within a similar time frame.
Altogether, the above data suggest that selective CBL-B inhibitors that display weak inhibition of c-CBL may potentially provide a therapeutic benefit with broad applications in cancer immunotherapy. While recent advances in immunology, pharmacology and data science have enabled scientists to develop better CBL-B inhibitors to meet this criterion, there remains a need for the invention of novel selective inhibitors as well as innovative therapeutic strategies to enhance their antitumor immunity in patients.
The compounds of formula 1 in this patent application are selective inhibitors of CBL-B. Particularly, they show greater inhibition of CBL-B than their inhibition of c-CBL, and that may be useful for the treatment, prevention, suppression and amelioration of cancer. These compounds may also be useful for the treatment of chronic viral infection or other diseases, disorders and conditions mediated by CBL-B.
Key Structures
The inventors described the structures
of 74 examples of formula 1 compounds as well as chemical procedures
for their synthesis. The following compounds are representative examples
of formula 1 structures.
Biological Assays
The inventors used the following assays to test the relevant biological activities of the compounds of formula 1:
Ligand Displacement Assay (LDA)
Surface Plasmon Resonance (SPR) Assay
Jurkat HiBit-IL2 Assay (WT, c-CBL KO, CBL-B KO)
Human PBMC Assay
Biological Data
The following table contains some of
the biological data obtained from testing the above representative
examples.
Recent Review Articles
The author declares no competing financial interest.
References
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