Cysteine covalent modifiers of AKT1 and uses thereof
Inventors
Chu, Hang • Reisberg, Solomon H. • Zajdlik, Adam • Yang, Kin S. • Carelli, Jordan D. • Thompson, Peter A.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12570655-B2
Publication Date
2026-03-10
Expiration Date
Abstract
Provided herein are covalent modifiers of AKT1 of Formula (I), (I-A), (II), (II-A), (III), (II-A), or (III-B), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating AKT1 using a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and pharmaceutical compositions thereof.
Core Innovation
The invention relates to compounds represented by Formula (I), or pharmaceutically acceptable salts thereof, with variable substituents including R1, A1, A2, R3, R4, Ring B, Ring D, and a linker L represented by -L1-L2-L3-L4-. A3 is a cysteine susceptible electrophile, and the structural scope is defined through explicit selections for rings, substituents, and linker components.
Ring B is selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, optionally substituted with listed substituent classes. Ring D is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, -OR12, -SR12, -N(R12)2, -NO2, and -CN. The linker L1-L2-L3-L4 is defined by group (a) and group (b) selections, with each L1-L4 optionally absent, no more than two of L1-L4 selected from group (a), and the two selected from group (a) not adjacent.
The disclosure also includes stereochemical and isotopic coverage for the Formula (I)/(I-A)/(II)/(II-A)/(III)/(III-A)/(III-B) compounds, together with salts, polymorphs/amorphous forms, and prodrugs. The compound scope further includes cysteine susceptible electrophile classes such as acrylate, acrylamide, vinylsulfone, vinylsulfonamide, ynamide, epoxide, haloacetamide, halotriazine, maleimide, nitrile, alkene, and alkyne, and describes covalent AKT1 protein embodiments.
Claims Coverage
The provided material explicitly identifies one independent compound claim and one therapeutic use claim. The compound claim centers on a Formula (I) scaffold with a cysteine susceptible electrophile as A3 and constrained ring/linker/substituent definitions; the therapeutic claim adds AKT1-modulated cancer treatment. In total, the consolidated claim coverage includes 4 inventive features.
Formula (I) compound scaffold
A compound represented by the structure of Formula (I), or a pharmaceutically acceptable salt thereof, with variable substituents including R1, A1, A2, R3, R4, Ring B, Ring D, and linker L.
Cysteine susceptible electrophile as A3
A3 is cysteine susceptible electrophile within the Formula (I) scaffold.
Constrained linker L as -L1-L2-L3-L4-
L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from group (a) or group (b), each optionally absent, no more than two are selected from group (a), and the two selected from group (a) are not adjacent.
Cancer treatment by AKT1 modulation
A method of treating cancer in a subject by administering a compound or salt of claim 1, or a pharmaceutical composition including a compound or salt of claim 1 with a pharmaceutically acceptable excipient, wherein the administration modulates wild-type AKT1 activity or mutant AKT1 activity, and the cancer is selected from prostate cancer, breast cancer, colorectal cancer, and meningioma.
The claim coverage is directed to Formula (I) compounds defined by a cysteine susceptible electrophile and a constrained ring/linker framework, and includes a treatment claim for specified cancers through modulation of wild-type or mutant AKT1 activity.
Stated Advantages
Provides stereochemical/isomeric coverage and isotopic labeling scope.
Includes isotopically enriched forms, salts, polymorphs/amorphous forms, and prodrugs.
Enables cancer treatment by modulating AKT1 activity, including wild-type AKT1 and mutant AKT1 E17K, through covalent AKT1 protein embodiments.
Selectively modulates AKT1 over AKT2.
Enables irreversible covalent bond formation at AKT1 cysteine residues C296 or C310.
Reduced off-target engagement, as associated with covalent-adduct single-residue binding to AKT1.
Selective modulation or inhibition of mutant AKT1 versus wild-type AKT1, including AKT1 E17K.
AKT1 activity attenuation reported as 50%–95%.
A fold-selectivity of 2–100-fold for AKT1 E17K versus wild-type AKT1 is reported.
Documented Applications
Cancer treatment by modulating AKT1 activity, including wild-type AKT1 and mutant AKT1 E17K.
Treatment of prostate cancer, breast cancer, colorectal cancer, and meningioma.
Covalent AKT1 protein embodiments with irreversible carbon-sulfur bond formation at AKT1 cysteine residues C296 or C310.
Treating cancer in a subject by administering a compound or salt of claim 1, or a pharmaceutical composition including a compound or salt of claim 1 with a pharmaceutically acceptable excipient, where the administration modulates wild-type AKT1 activity or mutant AKT1 activity; the cancer is selected from prostate cancer, breast cancer, colorectal cancer, and meningioma.
Interested in licensing this patent?