Compounds for targeted degradation of interleukin-2-inducible T-cell kinase and methods of use
Inventors
Gray, Nathanael S. • JIANG, Baishan • Weinstock, David • Wu, Wenchao
Assignees
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Publication Number
US-12678508-B2
Publication Date
2026-07-14
Expiration Date
Abstract
Disclosed are bispecific compounds (degraders) that target ITK or a zinc finger (ZnF) protein for degradation. Also disclosed are pharmaceutical compositions containing the degraders and methods of using the compounds to treat diseases and disorders characterized or mediated by ITK or ZnF protein activity.
Core Innovation
The claim covers bispecific compounds of formula (I) pairing an ITK/ZnF-targeting ligand with an E3 ubiquitin ligase-binding degron through an alkylene-chain or polyethylene-glycol-chain linker having specified interruptions or terminal groups. Degrons are selected from specified D1–D4 formula families, including cereblon-, VHL-, IAP-, and MDM2-binding structures, encompassing pharmaceutically acceptable salts and stereoisomers. Associated ZnF targets include IKZF1, IKZF3, ZFP91, RNF166, ZNF653, and ZNF692.
Compound 1 functions as a bifunctional degrader that degrades ITK dependent on E3-ligase activity and ITK binding. Experimental results show compound 1 inhibits DERL-2 cell proliferation, induces cell death while sparing Hut78 growth under test conditions, and mediates ITK degradation in Hut78 xenograft tumors. The compounds are utilized in pharmaceutical compositions for treating ITK- and/or ZnF-mediated diseases, alone or in combination therapies.
Claims Coverage
The provided relevant claims identify one independent claim, claim 1, covering three inventive features.
Compound of formula (I)
The compound pairs an ITK/ZnF-targeting ligand with an E3 ubiquitin ligase-binding degron, defined by specified alternatives for R1 and R2, and encompasses pharmaceutically acceptable salts and stereoisomers.
Specified degron structures
The degron has a structure selected from the D1a–j, D2-a–f, D3-a–c, or D4-a–b formula families, including specified substituent alternatives, ring systems, and stereoisomers.
Alkylene-chain or polyethylene-glycol-chain linker
The linker comprises an alkylene chain or a polyethylene glycol chain, either of which may be interrupted by or terminate at either or both termini in specified functional groups or ring systems.
The independent claim covers defined formula (I) bispecific compounds through specified R1 and R2 substituents, degron families, and linker alternatives, including pharmaceutically acceptable salts and stereoisomers.
Stated Advantages
Compound 1 rapidly degrades ITK and is reported to have greater potency for this effect than compound 2 or the parental inhibitor.
Compound 1 inhibits DERL-2 proliferation and induces cell death, while sparing Hut78 growth under the reported conditions.
Documented Applications
Pharmaceutical compositions comprising a therapeutically effective amount of a covered compound, salt, or stereoisomer and a pharmaceutically acceptable carrier.
Treatment of ITK- and/or ZnF-mediated diseases, including inflammatory myofibroblastic tumor, breast cancer, colorectal cancer, esophageal squamous cell cancer, renal cell cancer, melanoma, non-small cell lung cancer, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, mantle cell lymphoma, small lymphocytic lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, T-cell prolymphocytic leukemia, and T-cell large granular lymphocyte leukemia.
Administration alone or in combination with an additional therapeutic agent, including an immune effector cell expressing a chimeric antigen receptor.
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