Important Compound Classes
Title
Molecules and Methods Related to Treatment of Uncontrolled Cellular Proliferation
Patent Publication Number
WO 2021/022076 A1
Publication Date
February 04, 2021
Priority Application
62/881.774 US
Priority Date
August 01, 2019
Inventors
Min, J.; Jarusiewicz, J.; Actis, M.; Chang, Y.; Roberts, K.; Mullighan, C.; Rankovic, Z.
Assignee Company
St. Jude Children’s Research Hospital [US/US]: 262 Danny Thomas Place, Memphis, TN 38105, United States
Disease Area
Janus Kinase (JAK)
Biological Target
Cancer
Summary
Infections and allergies can trigger an initial phase of acute inflammation, and continued acute inflammation leads to chronic inflammation, which may culminate into tissue damage. Acute inflammation induces the infiltration of neutrophilic cells followed by monocytic cells, whereas chronic inflammation is characterized by the presence of mononuclear cells such as macrophages and lymphocytes at the site of inflammation. Various cytokines are produced during these processes and are mainly include the interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interferon-γ (IFN-γ), and transforming growth factor-β (TGF-β), which stimulate the production of acute phase proteins (APPs). IL-6 elicits acute phase reactions and also leads to the development of specific cellular and humoral immune responses via end-stage B-cell differentiation, immunoglobulin secretion, and T-cell activation. Consequently, IL-6 is an essential modulator for the transition from the acute phase to chronic phase of inflammation. IL-6 transmits a signal through mIL-6R (classical signaling pathway) or through sIL-6R (trans-signaling pathway). Classic signaling is manifested mainly in leukocytes and liver cells, which promote the anti-inflammatory responses. Whereas, trans-signaling leads to pro-inflammatory responses, which are elicited by a hexameric complex of IL-6. This hexameric complex activates JAK, which in turn activates three possible signaling pathways. JAK induces tyrosine phosphorylation of itself and subsequently activates dimerization of signal transducer and transcription-3 (STAT3). STATs are DNA-binding proteins, when phosphorylated, will dimerize and translocate to the nucleus. In another pathway, JAK activates the Ras/Raf pathway, which subsequently causes hyperphosphorylation of mitogen activated protein kinases (MAPK) and an increase in its serine/threonine kinase activity. Finally, activation of the phosphoinositol-3 kinase (PI3K)–protein kinase B (PKB)/Akt pathway occurs, wherein JAK phosphorylates and activates PI3K, which then phosphorylates certain phosphatidylinositides to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3, in turn, phosphorylates and activates PKB/Akt, which is recruited to the plasma membrane. Activation of STAT3, MAPK, PKB/Akt pathways, and NF-κB leads to varied pathological conditions such as cancer, multiple sclerosis (MS), rheumatoid arthritis (RA), diabetes, anemia, inflammatory bowel disease (IBD), Crohn’s disease (CD), and Alzheimer’s disease (AD).
JAKs are a family of enzymes that belong to the tyrosine kinase family which transduce cytokine-mediated signals. JAKs phosphorylate tyrosine residues which then activate downstream signaling proteins and induce physiological functions. When JAKs are activated, they transfer extracellular signals from cytokines, growth factors, and chemokines, which then are translated directly to change DNA transcription and translation of several proteins. JAK1, JAK2, and TYK2 are expressed by many cells, whereas JAK3 is express in hematopoietic, myeloid, and lymphoid cells.
This Patent Highlight shows representative PROTAC compounds bound to JAK2, where ruxolitinib and baricitinib bind to the human JAK2 JH1. Furthermore, representative data illustrate protein degradation, cytotoxicity, and effect of the JAK-STAT signaling pathway of the PROTAC compounds in MHH-CALL-4 cells.
Key Structures
Biological Assay
CRISPR-Cas9 editing, Caco-2 cell permeability assay, immunoblot analysis, cytotoxicity assay, xenograft, and in vivo preclinical studies.
Biological Data
The Table below shows EC50 values (in μM) for exemplary
compounds tested in MHH-CALL-4.
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The author declares no competing financial interest.