Arginine methyltransferase 5 (PRMT5) degraders and uses thereof
Inventors
Qi, Jun • Wu, Lei • Park, Paul M. • Sigua, Logan H.
Assignees
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Publication Number
US-12685776-B2
Publication Date
2026-07-21
Expiration Date
Abstract
Disclosed are to bifunctional compounds that target PRMT5 for degradation, compositions, and methods for treating diseases or conditions mediated by aberrant arginine methyltransferase 5 (PRMT5) activity.
Core Innovation
The disclosed invention is a bifunctional compound represented by formula (I), comprising a PRMT5-targeting ligand represented by TL1 or TL2 and an RPN13/ADRM1-binding degron or RA190-derived moiety. The degron and targeting ligand are connected through a linker comprising an alkylene chain or a polyethylene glycol chain. The compounds recruit PRMT5 to the ubiquitin–proteasome system for degradation, with permitted variations in linker composition and length, as well as pharmaceutically acceptable salts and stereoisomers.
Synthetic embodiments couple PRMT5-targeting moieties to RA190-derived ligands through varied alkyl, ether, piperazine, and polyethylene glycol linkers for pharmaceutical compositions. In screening results, the compounds inhibit PRMT5 activity and reduce PRMT5 protein in HEK293T cells, while compound 14 reduces PRMT5 and RPN13 in HL60 cells. The compounds are formulated for treating PRMT5-mediated disorders, including specified cancers, myelodysplastic syndrome, and acute myeloid leukemia, while the background problem is not explicitly described in patent.
Claims Coverage
The claims identify one independent claim comprising three inventive features.
Bifunctional compound represented by formula (I)
The claim covers a bifunctional compound represented by formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, with specified choices for R, X, and substituents R1 to R5.
Alkylene or polyethylene glycol linker
The linker comprises an alkylene chain that may be interrupted by or terminate in specified groups, or comprises a polyethylene glycol chain that may terminate in specified groups.
Targeting ligand represented by TL1 or TL2
The targeting ligand is represented by TL1 or TL2.
Claim 1 covers the specified bifunctional compound of formula (I) through its substituent choices, alkylene or polyethylene glycol linker alternatives, and TL1 or TL2 targeting ligand, including pharmaceutically acceptable salts and stereoisomers.
Stated Advantages
Not explicitly described in patent.
Documented Applications
The compounds are described for pharmaceutical compositions and the treatment of diseases or disorders characterized or mediated by aberrant PRMT5 activity, including specified cancers, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML).
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