Non-covalent modifiers of AKT1 and uses thereof
Inventors
Chu, Hang • Yang, Kin S. • Reisberg, Solomon H. • Zajdlik, Adam • Carelli, Jordan D. • Bestvater, Brian P. • Hansen, Timothy R. • Thompson, Peter A.
Assignees
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Publication Number
US-12624034-B2
Publication Date
2026-05-12
Expiration Date
Abstract
Provided herein are non-covalent modifiers of AKT1 of Formula (I), (II), (II-A), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), or (VI-B), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating wild-type AKT1 using a compound or salt of Formula (I), (II), (II-A), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), or (VI-B), and pharmaceutical compositions thereof.
Core Innovation
The disclosure provides compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, with a common scaffold defined by Ring B, R1, A1, A2, R2 through R5, and a linker L represented by L1-L4. The structural scope is set by extensive optional substitution patterns and ring selections, including heterocycle and carbocycle families, while preserving the same overall Formula (I) framework.
Ring B is selected from specified carbocycle, heterocycle, and alkyl options, and A1 and A2 are independently selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, alkynyl, carbocycle, heterocycle, and multiple oxygen-, sulfur-, nitrogen-, carbonyl-, and sulfonyl-containing substituent families. The scaffold further includes numerical parameters q, m, n, and p, and substituent variables R10 through R16, each selected from explicitly defined sets with additional optional substitution patterns.
The linker L is represented as L1-L2-L3-L4, with each linker element independently selected from heteroatom-containing link groups and carbon-based link groups, and with the constraints that linker elements may be absent, no more than two of L1-L4 are selected from the heteroatom-containing set, and any two selected from that set are not adjacent. R5 is selected from a 4- to 10-membered heterocycle or a C3-10 carbocycle, each optionally substituted with defined substituent families, and the document also includes pharmaceutically acceptable salts and example compounds within the same scaffold logic.
Claims Coverage
The consolidated claim coverage centers on one independent claim, Formula (I), with broad structural definition and dependent refinements. The inventive scope includes selectable ring systems, multiple variable substituent families, a constrained linker L composed of L1-L4, and additional narrowed embodiments for parameter values and ring selections.
Formula (I) compound or pharmaceutically acceptable salt
A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, defined by selectable ring systems and multiple variable substituents.
Ring B and R1 selection
Ring B is selected from specified carbocycle, heterocycle, and alkyl options, and R1 is selected from hydrogen, halogen, OR10, SR10, N(R10)2, NO2, CN, and optionally substituted carbocycle, heterocycle, and alkyl options.
A1 and A2 substituent families
A1 and A2 are each independently selected from hydrogen, halogen, haloalkyl, OR11, SR11, N(R11)2, carbonyl-containing groups, sulfonyl-related groups, nitro, cyano, alkyl, alkenyl, alkynyl, and optionally substituted carbocycle and heterocycle options.
Linker L defined by L1-L4
L is represented by L1-L2-L3-L4, where each Li is independently selected from heteroatom-containing link groups and carbon link groups, each optionally absent, with no more than two Li selected from the heteroatom-containing set and the selected ones not adjacent.
R2 through R5 variable substituents
R2, R3, R4, and R5 are independently selected from defined substituent sets, including halogen, OR, SR, N(R)2, carbonyl-containing groups, nitro, cyano, and heterocycle or carbocycle ring-forming options for R4 and R5.
Dependent parameter constraints
Dependent claims further narrow the scaffold by fixing values such as q, m, n, and p, and by restricting linker selection and R5 to specified heterocycle or carbocycle families.
Cancer treatment use
A method of treating cancer in a subject by administering the claimed compound or a pharmaceutical composition containing the compound with a pharmaceutically acceptable excipient.
Overall, the claim coverage is directed to Formula (I) compounds defined by broad but structured selection of Ring B, R1, A1/A2, R2-R5, and linker L, with dependent claims narrowing parameter values and structural options. The claim set also includes a therapeutic use for treating cancer.
Stated Advantages
Selectively modulating AKT1 over AKT2.
Inhibition of AKT1, including modulation of mutant AKT1 activity and wild-type AKT1 activity.
Therapeutic treatment of cancer.
Provides pharmaceutical composition forms including pharmaceutically acceptable salts, solvates/hydrates, polymorphs, and prodrugs.
Documented Applications
Treating cancer in a subject by administering the Formula (I) compound or salt, or a pharmaceutical composition containing the compound or salt with a pharmaceutically acceptable excipient.
Treating breast cancer.
Treating colorectal cancer.
Treating meningioma.
AKT1 inhibition and AKT1/AKT2 target engagement profiles are documented for representative compounds.
Therapeutic context for AKT1 inhibition, including modulation of mutant AKT1 activity and wild-type AKT1 activity, in the context of cancer.
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