Rapafucin derivative compounds and methods of use thereof
Inventors
Liu, Jun • Hong, Sam • Ullman, Brett R. • Semple, Joseph E. • YAMAMOTO, Kana • Kumar, Puneet • Sadagopan, Magesh • Schmitt, Jennifer C.
Assignees
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Publication Number
US-12540144-B2
Publication Date
2026-02-03
Expiration Date
Abstract
The present disclosure provides macrocyclic compounds inspired by the immunophilin ligand family of natural products FK506 and rapamycin. The generation of a Rapafucin library of macrocycles that contain FK506 and rapamycin binding domains should have great potential as new leads for developing drugs to be used for treating diseases.
Core Innovation
The invention relates to a tagged compound comprising a macrocyclic compound according to Formula (XII) linked with a compound according to Formula (XIV), optionally as a pharmaceutically acceptable salt or stereoisomer. The macrocyclic compound is constrained by Ring A, Ring B, and Ring C size and substituent definitions, together with defined linkage elements and heteroatom-containing connection options that connect the macrocyclic framework to the Formula (XIV) component.
A further defining aspect is the Effector Domain, which is expressed by alternative formula classes including Formula (XIIa), Formula (XIIb), Formula (XIIc), Formula (XIId), Formula (XIIe), and Formula (XIIf). These alternatives are parameterized by integer and binary variables and define Ring E as phenyl or a 5-6 heteroaryl or heterocycloalkyl, with selected bond, alkylene, alkenylene, alkynylene, sulfur-containing, and amide-like linkage options within the stated structural classes.
The tagged compound further includes an oligonucleotide (D) linked to at least one of X-V1-W-V2-Z, L1-L2-L3-L4-L5, L6-L7-L8, or the effector domain of Formula (XII). The claim also includes a conditional limitation for the case when Ring A is ethylene, with specified relationships among X, W, V1, V2, Z, and the stated linker segments.
Claims Coverage
One independent claim is provided. It covers a tagged compound comprising a macrocyclic compound of Formula (XII) linked to a compound of Formula (XIV), with four major inventive feature groups: constrained ring definitions, defined linker and connectivity architecture, an Effector Domain selectable among alternative formula classes, and an oligonucleotide linkage requirement.
Tagged compound comprising macrocyclic Formula (XII) linked to Formula (XIV)
A tagged compound comprising a macrocyclic compound according to Formula (XII) linked with a compound according to Formula (XIV), optionally as a pharmaceutically acceptable salt or stereoisomer thereof.
Ring A, Ring B, and Ring C structural constraints
Ring A is a 5-10 membered aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted with 1-17 substituents; Ring B is a 4-10 membered heterocycloalkyl optionally substituted with 1-10 substituents; and Ring C is a 5-6 membered heteroaryl optionally substituted with 1-4 substituents.
Defined linker and connection architecture
L-type elements including La, Lb, Lc, and L1-L8 are independently selected from bond and heteroatom-containing linker options, including O-, S-, carbonyl-containing, and substituted or unsubstituted alkylene-based connections, with additional optional substitution rules for alkylene segments.
Effector domain selectable among Formula classes XIIa-XIIf
The Effector Domain has Formula (XIIa), (XIIb), (XIIc), (XIId), (XIIe), or (XIIf), with defined integer and binary parameters and Ring E defined as phenyl or a 5-6 heteroaryl or heterocycloalkyl.
Oligonucleotide linkage to specified regions or the effector domain
The oligonucleotide (D) is linked to at least one of X-V1-W-V2-Z, L1-L2-L3-L4-L5, L6-L7-L8, or the effector domain of Formula (XII), with a conditional limitation for the Ring A is ethylene case.
The claim coverage is anchored in a tagged compound that combines a macrocyclic compound of Formula (XII) with a compound of Formula (XIV), while defining ring systems, linker architecture, an Effector Domain with alternative formula classes, and a required oligonucleotide linkage to selected regions or the effector domain.
Stated Advantages
Documented Applications
Screening compounds for treating cancer or autoimmune disease using hybrid cyclic libraries in the FK506/rapamycin immunophilin ligand family.
DNA-encoded and/or solid-phase library synthesis contexts are explicitly referenced through resin support and oligonucleotide (D) attachment/linking.
A DNA-encoded library binding/selection workflow involving incubation with a biological target, removal of unbound compounds, and sequencing of oligonucleotide D is described.
A family of Rapafucin molecules using Formula (XV) is described with tables listing variants characterized by retention time and relative proliferation/uptake categories across cell lines including A549, NCI-H929, and 293T.
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