Important Compound Classes
Title
Compounds and Methods for the Targeted Degradation of Interleukin-1 Receptor-Associated Kinase 1 Proteins
Patent Publication Number
WO 2021/018118 A1
Publication Date
February 04, 2021
Priority Application
PCT/CN2019/098203
Priority Date
July 29, 2019 CN
Inventors
Fu, L.; Zhang, J.; Tu, W.; Liu, Y.; Kong, L.; Shen, B.; Dai, X.; Xu, Y.
Assignee Company
Janssen Pharmaceutica NV [BE/BE]; Turnhoutseweg 30, 2340 Beerse, Belgium
Disease Area
Interleukin-1 Receptor-Associated Kinase 1 (IRAK1)
Biological Target
Cancer
Summary
The interleukin-1 receptor-activated kinase 1 (IRAK 1) belongs to a family of four serine/threonine kinases, which are essential mediators of IL-1R signaling process and are implicated in innate immunity and inflammatory responses. IRAK1, IRAK2, and IRAK4 are expressed in a variety of cell types, while IRAK3 (also known as IRAK-M) is mainly expressed in cells of monocytic origin. All four kinases have a similar domain structure, which include an N-terminal death domain (where dimerization and MyD88 interaction occurs), a proline/serine/threonine-rich (ProST) domain, a kinase/pseudokinase domain, and a C-terminal domain except for IRAK4. IRAK4 and IRAK1 have intrinsic kinase activities, whereas IRAK2 and IRAK-M are apparently pseudokinases.
IRAKs are key regulators of pro-inflammatory signaling that are elicited by the Toll-like receptors (TLRs), interleukin-1 receptor (IL-IR), and interleukin-18 receptor. Upon ligand recognition, TLRs or IL-1/-18Rs dimerize and undergo conformational changes, allowing their intracellular domains to recruit the myeloid differentiation primary response 88 (MyD88) adaptor protein. Numerous MyD88 molecules oligomerize through N-terminal death domains (DD) and recruit DD domain-containing IRAKs, forming a macromolecular signaling complex, termed the myddosome, which results in autophosphorylation and activation of IRAK4. Activated IRAK4 then phosphorylates IRAK1 and/or IRAK2, followed by the transient recruitment of TNFR-associated factor 6 (TRAF6) to the myddosome. Consequently, TRAF6 is then activated and released to the cytosol, where it triggers the activation of the IκCB kinase (IKK)-nuclear factor-κB (NF-KB) cascades and the MAP kinase (MAPK) signaling pathways. As a result, it leads to the transcription of multiple potent pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-10 (IL-10), as well the production of various chemokines.
In vivo experiment has shown that mice lacking IRAK1 are viable and healthy, appeared indistinguishable from wild-type heterozygous littermates, and demonstrated normal physiology with organs normal in size and morphology. When infused with TLR agonists, deletion of IRAK attenuates but does not eliminate cytokine responsiveness in mutant mice and cells. In human, inherited IRAK1 deficiency appeared to be different from IRAK4 or MyD88 deficiency with no evident of bacterial infection. The fibroblasts isolated from an IRAK1 deficient patient respond poorly to TLR agonists but remained normal to IL-1b, and the patient’s peripheral blood mononuclear cells responded normally to all TLR agonists and IL-lb. These findings may suggest that the human IRAK1 may play a redundant downstream role from TLRs/IL-1Rs and Myd88 innate immune responses.
In oncology, MyD88 was found to be mutated in 39% of patients with an aggressive subtype of B cell lymphoma, the active B cell-like diffuse large B cell lymphoma (ABC DLBCL). The same somatic mutation of MyD88 was also detected in other types of B cell malignancies, including Wald Enstrom’s macroglobulinemia, primary central nervous system lymphomas, and IgM-secreting lymphoplasmacytic lymphoma.
In spite of all these developments, IRAK1 remains a challenging target using traditional small molecule inhibitors, due in part to lack of understanding about the domain that is mainly responsible for its scaffolding function. In addition, there are no reports on its druggable pocket outside its kinase domain. An increasingly important therapeutic strategy is the proteolysis targeting chimera (PROTAC), which are large bifunctional molecules, in which a ligand for an E3 ligase is connected to a specific binder of a protein of interest (POI) via a flexible linker. However, their chimeric nature allows for high specificity. In this Patent Highlight, the heterobispecific small molecules recruit E3 ligase which induces IRAKI protein degradation and eliminates its scaffolding function. In particular, this can be used as prophylaxis or in the treatment of neurodegenerative disease, inflammatory disease, or cancer mediated by IRAK1.
Key Structures
Biological Assay
Western Blot and HiBit assays
Biological Data
The Table below show DC50, when the concentration at which
50% IRAK1 degradation was observed
after treatment. The Dmax indicate the
maximal level of IRAK1 protein degradation after compound treatment
at 10 μM for 24 h.
Recent Review Articles
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1.
Su L.; Xu W.; Huang A.. Autoimmun. Rev. 2020, 19, 102461.
The author declares no competing financial interest.