Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
Inventors
Crew, Andrew P. • Araujo, Erika
Assignees
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Publication Number
US-11065231-B2
Publication Date
2021-07-20
Expiration Date
Abstract
The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
Core Innovation
The invention relates to bifunctional compounds having the chemical structure PTM-L-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof. The chemical linker group L covalently couples the PTM to the ULM, and the ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM). The PTM is a small molecule comprising an Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) targeting moiety represented by PTM-Va or PTM-Vb, and the PTM is modified to be covalently joined to the chemical linker group.
The CLM structure is defined by variable selections for W, X, Y, Z, G and G', Q1-Q4, A, n, R, and related indices, with one R group modified to be covalently joined to the PTM or the chemical linker group. The PTM-Va/PTM-Vb structures are defined by X1-X3, Y, ring Z, A, and multiple substituent variables R1-R9 and R9a, with covalent joining points specified by modification of Y or selected R groups.
The disclosure further includes linker and PTM structural embodiments, including polyethylenoxy/polyether-type groups and repeat structural units. It also includes representative PTM and linker examples and structural examples showing covalent joining between the IRAK-4 targeting moiety and the cereblon E3 ubiquitin ligase binding moiety through L.
Claims Coverage
The consolidated claim coverage identifies one independent claim family directed to a bifunctional PTM-L-ULM compound with a chemical linker covalently coupling an IRAK-4 targeting moiety to a cereblon E3 ubiquitin ligase binding moiety. The inventive features repeatedly emphasized across the input are the PTM-L-ULM architecture, the defined CLM/ULM structural framework, the defined PTM-Va/PTM-Vb structural framework, and the covalent attachment points to the linker.
Bifunctional PTM-L-ULM architecture
A bifunctional compound having the chemical structure PTM-L-ULM, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, or polymorph thereof, wherein L is a chemical linker group that covalently couples the ULM to the PTM.
Cereblon E3 ubiquitin ligase binding moiety structural framework
The ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM) with variable selections for W, X, Y, Z, G and G', Q1-Q4, A, n, and R, and one R group is modified to be covalently joined to the PTM or the chemical linker group.
IRAK-4 targeting moiety PTM-Va or PTM-Vb
The PTM is a small molecule comprising an Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4) targeting moiety represented by PTM-Va or PTM-Vb, with variable selections for X1, X2, X3, Y, ring Z, A, R1 through R9 and R9a, and the selected PTM variables are modified to be covalently joined to the chemical linker group.
Polyethylenoxy and repeat linker embodiments
The linker L includes embodiments described as polyethylenoxy/polyether-type groups and repeat structural units, with linker architectures that covalently couple the ULM to the PTM.
Overall, the claims center on a bifunctional PTM-L-ULM compound in which an IRAK-4 targeting PTM-Va or PTM-Vb is covalently linked through L to a cereblon E3 ubiquitin ligase binding moiety, with broad structural variable definitions and explicit covalent attachment requirements.
Stated Advantages
Protein level control via target protein degradation in cells and in vivo.
Induces ubiquitination and proteasomal degradation of the target protein.
Inhibits activity.
Documented Applications
IRAK PROTAC molecules for protein level control via IRAK4-targeting target protein degradation in cells.
Therapeutic use for diseases linked to aggregation/accumulation of target proteins including IRAK-4.
Treatment methods involving diseases or disorders associated with IRAK-4 accumulation and aggregation.
Pharmaceutical compositions comprising an effective amount of a bifunctional compound together with a pharmaceutically acceptable carrier.
Protein level control through target protein degradation in cells and in vivo.
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