Compounds that participate in cooperative binding and uses thereof
Inventors
VERDINE, Gregory Lawrence • BOWMAN, Brian Roger • SOWA, Mathew Edward • BLODGETT, Joshua Alan Van Dyke • Robison, Keith Earl • STILES, Dylan Talbot • MORGENSTERN, Jay Paul • TOWNSON, Sharon Ann • SHIGDEL, Uddhav Kumar
Assignees
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Publication Number
US-11987590-B2
Publication Date
2024-05-21
Expiration Date
Abstract
The invention features compounds (e.g., macrocyclic compounds) capable of modulating biological processes, for example through binding to a presenter protein (e.g., a member of the FKBP family, a member of the cyclophilin family, or PIN1) and a target protein such as CEP250. These compounds bind endogenous intracellular presenter proteins, such as the FKBPs or cyclophilins, and the resulting binary complexes selectively bind and modulate the activity of the target protein. Formation of a tripartite complex among the presenter protein, the compound, and the target protein is driven by both protein-compound and protein-protein interactions, and both are required for modulation of target protein activity.
Core Innovation
A macrocyclic compound, or a pharmaceutically acceptable salt thereof, comprises a target protein interacting moiety and a presenter protein binding moiety. The compound and a presenter protein form a complex that specifically binds to a target protein, and each of the compound and the presenter protein do not substantially bind to the target protein in the absence of forming the complex. Alternatively, the complex binds to the target protein with at least 5-fold greater affinity than the affinity of each component in the absence of forming the complex.
The target protein interacting moiety comprises the structure of Formula XIII, wherein dotted lines represent zero to three double bonds and no two double bonds are adjacent to one another. R31 and R32 are independently selected from the listed groups and may alternatively combine to form C=O, and R33 is hydrogen or C=O, with the constraint that no double bond is adjacent to a C=O.
The presenter protein binding moiety comprises the structure of Formula I, wherein n is 0 or 1; X1 and X3 are each independently O, S, CR3R4, or NR5; and X2 is O, S, or NR5. R1, R2, R3, R4, and R5 are selected from the listed functional groups and can form optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl when taken together with the atoms to which they are bound, with further constraints described for combinations including R5 and one of R1-R4.
Claims Coverage
The provided independent claim coverage centers on one macrocyclic compound design with a target protein interacting moiety and a presenter protein binding moiety, together with complex-dependent specific binding and/or at least 5-fold affinity enhancement. Three inventive features are consistently supported across the items.
Complex-dependent target protein binding
A macrocyclic compound, or a pharmaceutically acceptable salt thereof, includes a target protein interacting moiety and a presenter protein binding moiety, wherein the compound and a presenter protein form a complex that specifically binds to the target protein and each of the compound and the presenter protein do not substantially bind to the target protein in the absence of forming the complex.
At least 5-fold greater complex affinity
The compound and a presenter protein form a complex that binds to the target protein with at least 5-fold greater affinity than the affinity of each component to the target protein in the absence of forming the complex.
Structure of Formula XIII and Formula I
The target protein interacting moiety comprises the structure of Formula XIII, with dotted lines representing zero to three double bonds and no two double bonds adjacent to one another, and the presenter protein binding moiety comprises the structure of Formula I, wherein n is 0 or 1; X1 and X3 are each independently O, S, CR3R4, or NR5; X2 is O, S, or NR5; and the substituents are defined with the stated ring-forming and substitution constraints.
Across the provided material, the claim coverage centers on macrocyclic compounds that bind a target protein through presenter-protein complex formation, with binding defined either by absence of substantial individual binding or by at least 5-fold greater complex affinity, and with structural constraints imposed by Formula XIII and Formula I.
Stated Advantages
The complex specifically binds to the target protein.
Each of the compound and the presenter protein does not substantially bind to the target protein in the absence of forming the complex.
The complex binds to the target protein with at least 5-fold greater affinity than the affinity of each component to the target protein in the absence of forming the complex.
Documented Applications
Treatment or modulation related to CEP250, including CEP250-associated signaling, ciliopathy, and cancer contexts.
Inhibition of prolyl isomerase activity by contacting a cell expressing prolyl isomerase with the compound.
Modulating a target protein by contacting a cell expressing the target protein with a presenter protein and an effective amount of the compound, where the resulting complex binds the target protein to modulate it.
Binding characterization of FKBP12 and FKBP12-compound complexes to target protein CEP250, including AlphaLISA displacement affinities, SPR kinetic Kd values, ITC thermodynamic conclusions, and crystallographic structural determination of ternary complexes involving FKBP12/compound/CEP250.
Reported cell permeability using IC50 for selected compounds.
Therapeutic or functional uses related to centrosome/centriole cohesion.
Therapeutic or functional uses related to cilia/ciliopathies.
Therapeutic or functional uses related to signaling pathways including Hedgehog, Wnt, PDGFRα, and integrin.
Therapeutic or functional uses related to cancer and infections.
Inhibiting prolyl isomerase activity by contacting a cell expressing a prolyl isomerase with a compound so the compound forms a complex with the prolyl isomerase.
Modulating a target protein by contacting a cell expressing the target protein with a presenter protein and an effective amount of the compound, where the complex binds the target protein to modulate it.
Targeting the protein CEP250 using the claimed compound.
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