Methods and compositions for irreversible enzyme inhibition
Inventors
Sporn, Michael B. • Meng, Xiaoli
Assignees
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Publication Number
US-12551562-B2
Publication Date
2026-02-17
Expiration Date
Abstract
The present invention relates to compounds, methods, and compositions for irreversibly inhibiting protein targets, including Keap1 and/or LONP1 protease. In certain aspects, the present invention relates to conjugates and/or cross-linked conjugates comprising a protein or a protein complex and a bifunctional triterpenoid, such as 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (“CDDO-2P-Im”), 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole (“CDDO-3P-Im”), or derivatives thereof.
Core Innovation
The invention relates to irreversible inhibition of protein targets by bifunctional triterpenoids that form covalent conjugates and cross-linked conjugates with protein amino-acid residues. The conjugates are covalently and irreversibly linked to nucleophilic amino acid residues contained in proteins, including cysteine and amino acid residues selected from lysine, serine, arginine, and tyrosine.
The described protein targets include human Keap1 and human LONP1, with specified target-residue mappings for covalent attachment. For human Keap1, covalently modified residues include Cys38, Tyr85, Tyr208, Cys257, Tyr263, Cys288, Lys323, and Tyr443. For human LONP1, covalently modified residues include Lys426, Tyr473, Cys520, Cys637, Tyr673, Cys682, Lys718, and Lys896.
The invention further includes method aspects centered on irreversibly inhibiting protein activity in a patient or in a biological sample by administering or contacting with CDDO-2P-Im or a pharmaceutically acceptable salt thereof. Covalent inhibition is described as modification of nucleophilic amino acid residues contained in the proteins, with mechanisms described via Michael addition to cysteine and acylation of lysine, serine, arginine, and tyrosine.
Claims Coverage
The document includes five independent claims. Across these claims, the inventive coverage centers on cross-linked conjugates and defined structures, covalent irreversible conjugates via nucleophilic residues to a synthetic triterpenoid, methods for irreversibly inhibiting protein activity in a patient or biological sample using CDDO-2P-Im, and disease treatment methods, including neurodegenerative disease and cancer patient embodiments. The claims enumerate nucleophilic residue attachment points and define structural forms corresponding to Formula (I) and Formula (II), and they specify protein targets including human GSTP, human Keap1, human LONP1, and human PPIA.
Cross-linked conjugate with bifunctional triterpenoid covalently linked to at least two amino acid residues
A cross-linked conjugate comprising a bifunctional triterpenoid covalently linked to at least two amino acid residues of a protein.
Method for irreversibly inhibiting protein activity using CDDO-2P-Im via covalent modification of a nucleophilic residue
A method for irreversibly inhibiting the activity of a protein in a patient or in a biological sample by administering to said patient or contacting said biological sample with CDDO-2P-Im or a pharmaceutically acceptable salt thereof, wherein the protein activity is irreversibly inhibited by covalently modifying a nucleophilic amino acid residue contained therein, and wherein the protein is human GSTP, human Keap1, human LONP1, or human PPIA.
Conjugate with nucleophilic residue covalently and irreversibly bonded to a synthetic triterpenoid defined by Formula (I)
A conjugate comprising a protein having a nucleophilic residue, wherein the nucleophilic residue is covalently and irreversibly bonded to a synthetic triterpenoid, wherein said conjugate has a structure corresponding to Formula (I) with attachment through the nucleophilic residue and X represents O or N(H).
Method of treating neurodegenerative disease mediated by a protein using CDDO-2P-Im
A method of treating a disease or condition mediated by a protein, comprising administering to a patient in need thereof a therapeutically effective amount of CDDO-2P-Im or a pharmaceutically acceptable salt thereof, wherein the disease or condition is a neurodegenerative disease and wherein the protein is human GSTP, human Keap1, human LONP1, or human PPIA, and wherein the compound irreversibly inhibits the protein.
Cross-linked conjugate with cysteine and lysine/serine/arginine/tyrosine covalently bonded to synthetic bifunctional triterpenoid defined by Formula (II)
A cross-linked conjugate comprising one or more proteins, said one or more proteins having (i) a cysteine residue and (ii) a lysine, serine, arginine, or tyrosine residue, wherein the lysine, serine, arginine, or tyrosine residue is covalently and irreversibly bonded to a synthetic, bifunctional triterpenoid, wherein said conjugate has a structure corresponding to Formula (II) with attachment points through the lysine, serine, arginine, or tyrosine residue and through the cysteine residue, and X represents O or N(H).
Overall, the claim set covers covalently and irreversibly formed conjugates and cross-linked conjugates between synthetic bifunctional triterpenoids and protein nucleophilic residues, including defined structural forms corresponding to Formula (I) and Formula (II) with attachment-point conventions. It further covers methods that irreversibly inhibit protein activity in a patient or biological sample and includes treatment of neurodegenerative disease mediated by target proteins, with enumerated protein targets including human GSTP, human Keap1, human LONP1, and human PPIA.
Stated Advantages
Irreversibly inhibits the activity of a protein.
Covalently modifies nucleophilic amino acid residues contained in the protein.
Provides single and cross-linked adducts (cross-linked conjugates).
Enables covalent inhibition via Michael addition to cysteine and acylation of lysine, serine, arginine, and tyrosine.
Documented Applications
Downstream protein target profiling in B cells for CDDO-2P-Im [procedural detail omitted for safety].
Treating a neurodegenerative disease mediated by a protein using CDDO-2P-Im, with protein targets including human GSTP, human Keap1, human LONP1, or human PPIA.
Using methods for irreversibly inhibiting protein activity in a patient, including embodiments directed to cancer patients, with protein targets including human GSTP, human Keap1, human LONP1, or human PPIA.
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