Therapeutic Modulation of NLRP3 for Treatment of Cancer, Alzheimer’s Disease, and Trauma

Important Compound Classes

Title

Macrocyclic Sulfonylamide Derivatives Useful as NLRP3 Inhibitors

Patent Publication Number

WO 2021/032588 A1

Publication Date

February 25, 2021

Priority Application

1911781.1; 2004682.7; 2007669.1; 2010792.6 GB

Priority Date

August 16, 2019; March 31, 2020; May 22, 2020; July 14, 2020

Inventors

Cooper, M.; Miller, D.; Macleod, A.; Thom, S.; Shannon, J.; Incerti-pradillos, C.; Mcpherson, C. G.

Assignee Company

INFLAZOME Limited [IE/IE]; 88 Harcourt Street, Dublin 2 (IE)

Disease Area

Cancer, inflammasome, and autoimmune diseases.

Biological Target

Nod-like Receptor Protein 3 (NLRP3)

Summary

Multicellular organisms have two distinct types of immune responses against pathogens or foreign invaders. The innate, faster immune system is the first line of host defense employs the engagement of germline-encoded pattern-recognition receptors (PRRs) that activate it in response to harmful stimuli. PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), which are generated by endogenous stress, and trigger downstream inflammatory pathways to eliminate microbial infection and repair damaged tissues. The activation of inflammasomes is a major inflammatory pathway that activate inflammatory caspase-1 via a group of intracellular multimeric protein complexes. Five members of PRRs form the inflammasomes: the nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR) containing proteins, NLR family members NLRP1, NLRP3, and NLRC4, as well as absent-in-melanoma 2 (AIM2) and pyrin.

Nod-like receptor protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex responsible for numerous innate immune processes related to infection, inflammation, and autoimmunity. It consists of NLRP, apoptosis-associated speck-like protein containing caspase activation and recruitment domain (ASC), and caspase-1. The activation of NLRP3 inflammasomes leads to cleavage of pyroptosis-related protein gasdermin D, the production of proinflammatory cytokine IL-1β, and the overactivation of microglia. Furthermore, NLRP3 binds to apoptosis-associated speck-like protein that contain a caspase ASC. ASC then polymerizes to form a large aggregate (ASC speck), which interacts with the cysteine protease caspase-1 and form the inflammasome. Consequently, caspase-1 is activated and cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18. Caspase-1 also mediates pyroptosis, an inflammatory cell death. In human cells, caspase-1 may control the processing and secretion of IL-37. NLRP3 inflammasome can be regulated by the sirtuin 1 (SIRT1) signal, a class III histone deacetylase, which acts on the NLRP3 inflammasome through its interactions with NF-κB. NF-κB is a transcription factor that is critical for the development of numerous inflammatory responses, and when it is activated, NF-κB translocates into the nucleus and increases the translation of IL-1β and NLRP3. SIRT1 signaling is known to deactivate deacetylate p65 subunit of NF-κB at Lys310 and invariably deactivate the NLRP3 inflammasome. The NLRP3 inflammasome is reported to be implicated in the pathogenesis of depression, and it may serve as a novel therapeutic strategy for depression. There are some anti-inflammatory therapies that exhibit positive antidepressant actions, which reenforces the link between depression and inflammation. NLRP3, caspase-1, and IL-1β levels were found to be increased in the blood samples of patients with depression. In addition, the aberrant activity of NLRP3 is pathogenic in inherited disorders such as Alzheimer’s disease, multiple sclerosis, type 2 diabetes, and atherosclerosis. Mutations in NLRP3 are associated with the hereditary cryopyrin-associated periodic syndrome (CAPS) diseases; Muckle-Wells syndrome, familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID). NLRP3 is shown to play an emerging role in diseases of the central nervous system, lung, liver, kidney, and aging.

There are several small molecules that inhibit the NLRP3 inflammasome. For example, glyburide inhibits IL-1β production at micromolar concentrations in response to the activation of NLRP3 but not NLRC4 or NLRP1. Furthermore, weak inhibitors include 3,4-methylenedioxy-β-nitrostyrene, parthenolide, and dimethyl sulfoxide. Biological agents that target IL-1 are current treatments for NLRP3-related diseases. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody cankinumab, and the soluble decoy IL-1 receptor rilonacept. However, there is a need to provide compounds with improved pharmacological and favorable physicochemical properties.

The present patent highlight showcases exemplary compounds and methods to treat or prevent a number of diseases or disorders that are responsive to NLRP3 inhibition. For instance, cancer (acute lymphocytic leukemia, anal cancer), inflammation (relating to infection, trauma, injury, or autoimmunity), autoimmune disease (Addison’s disease, Crohn’s disease, type 1 diabetes, pediatric Celiac disease, Gravis’ disease), infections (viral infections, HIV, alphavirus), central nervous system diseases (Alzheimer’s disease, dementia, Parkinson’s, Huntington’s disease, traumatic brain injury), and so forth.

Key Structures

Biological Assay

THP-₁ cells pyroptosis assay and human whole blood IL-1β release assay.

Biological Data

The table below shows NLRP3 inhibitory activity, where +++++ = ≤0.1 μM, ++++ = ≤0.5 μM, +++ = ≤1 μM, and human whole blood (HWB) assay IC₅₀ values.

Recent Review Articles

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The author declares no competing financial interest.