Small molecule RPN13 inhibitors with antitumor properties
Inventors
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Assignees
Member
Johns Hopkins UniversityFounded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Founded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Publication Number
US-12673918-B2
Publication Date
2026-07-07
Expiration Date
Abstract
Compounds of formula (I), (II), and (III) having the structure shown below are presented: wherein R-R6 are defined herein. These molecules work as proteasome inhibitors and bind to the RPN13 subunit of the 19S regulatory particle, and can be used in methods of treating a condition or a disease, such as cancer, in a mammal.
Core Innovation
The invention relates to small-molecule ubiquitin-proteasome system inhibitors that target the RPN13 subunit of the 19S regulatory particle (19S RP) of the 26S proteasome. The compounds are based on Michael-acceptor bis-benzylidene piperidone/cyclohexanone scaffolds and are defined as compounds of formulas (I), (II), and (III), with provisions for pharmaceutically acceptable salts, hydrates, and solvates.
The patent also describes a class of compounds of formula (I) having variable groups R, R1, R2, R3, and n. The invention includes specific substituent options, including R selected from H, C(O)CH2Cl, C(O)CH3, C(O)CH2CH2Cl, or C(O)N(H)CH3; R1 independently selected from NO2 and halogen; R2 as a side group from an alpha amino acid; R3 as C1-C6 alkyl or phenyl; and n as an integer from 0-5 inclusive.
The disclosed examples and structure-activity relationship discussion include RA190-derived small-molecule analogs, such as RA181C, RA190B, RA190H, RA338, RA334, RA335, RA336, RA337, RA339, RA371, RA375, RA413S, and RA414. The document reports target labeling of RPN13 in HeLa lysates, differential competition among analog classes, rapid accumulation of polyubiquitinated proteins, and structure variations that affect target labeling and cytotoxic activity.
The description further reports ubiquitin-chain topology effects, with RA compounds differentially increasing K48-linked substrates while not increasing K63-linked polyubiquitinated proteins, and including K33-linked and K11-linked proteins in the topology context. RA375 is reported as an RPN13 inhibitor with strong pharmacodynamics, and the discussion links this class to solid cancers and to an orthotopic human ovarian cancer xenograft.
Claims Coverage
The consolidated claim coverage centers on one independent compound claim for formula (I) and dependent therapeutic method claims. In total, the independent coverage captures a structurally defined genus with five variable elements, while the dependent coverage adds a substitution-specific constraint, a stereochemical/compositional constraint, treatment of mammalian disease, cancer-specific selection, and optional combination therapy; no additional independent inventive feature is clearly separated in the provided text.
Compound of formula (I) with defined substituents
A compound of formula (I) wherein R is H, C(O)CH2Cl, C(O)CH3, C(O)CH2CH2Cl, or C(O)N(H)CH3; R1 at each occurrence is independently selected from NO2 and halogen; R2 is a side group from an alpha amino acid; R3 is C1-C6 alkyl or phenyl; and n at each occurrence is an integer from 0-5 inclusive. The compound includes pharmaceutically acceptable salt, hydrate, or solvate forms.
Specific constraint for the benzyl side group from phenylalanine
When R2 is the benzyl side group from phenylalanine and R3 is hydrogen, R is C(O)CH2Cl.
Carbon 2 stereochemical or mixture constraint when R3 is methyl
When R3 is methyl, the configuration at Carbon 2 of formula (I) is either the R configuration, the S configuration, or an equimolar mixture of R and S.
Treatment of a condition or disease in a mammal
A method for treating a condition or disease in a mammal by administering a therapeutically effective dose of the compound of claim 1 to the mammal.
Cancer-specific treatment selection including HPV-associated cancer
The method is limited to treating a cancer selected from a specified group of cancer types, including a cancer associated with Human Papilloma Virus (HPV).
Combination therapy with a proteasome inhibitor or DNA damaging agent
The method includes an additional therapeutic agent that is either a proteasome inhibitor or a DNA damaging agent, specifically bortezomib or cisplatin.
Overall, the claim coverage centers on a defined formula (I) compound with enumerated substituent options and coverage of pharmaceutically acceptable salts, hydrates, and solvates. The dependent coverage further narrows the compound by a phenylalanine-related substitution rule and a Carbon 2 stereochemical or mixture constraint, and extends to therapeutic methods for mammalian disease treatment, including selected cancers such as HPV-associated cancer, with optional combination therapy using bortezomib or cisplatin.
Stated Advantages
Structure-dependent differences in target binding competition with a 42 kDa cellular target identified as RPN13.
Comparative potency, cytotoxicity, and biological effect context including induction of polyubiquitinated proteins, glutathione depletion, increased ROS, unresolved ER stress, apoptosis markers, NF-κB inhibition, and mitochondrial bioenergetic/ATP depletion effects.
In vivo tolerability and pharmacodynamics using 4UbFL luciferase proteasome activity reporters, with xenograft and syngeneic ovarian tumor efficacy through tumor burden reduction and survival benefit.
Strong pharmacodynamics is reported for RA375.
Reduced tumor burden is reported in an orthotopic human ovarian cancer xenograft.
Increased survival is reported in an orthotopic human ovarian cancer xenograft.
RA compounds differentially increase K48-linked substrates while not increasing K63-linked polyubiquitinated proteins.
Documented Applications
Treating a condition or disease in a mammal by administering a therapeutically effective dose of the compound of claim 1.
Treating cancer selected from a specified group of cancer types, including a cancer associated with Human Papilloma Virus (HPV).
Combination treatment where the method includes an additional therapeutic agent that is either a proteasome inhibitor or a DNA damaging agent, specifically bortezomib or cisplatin.
Nonclinical and cell-based characterization of RA375, RA413S, and RA414, including HeLa and SKOV3 assay context and animal studies.
Anticancer performance described for bortezomib-resistant multiple myeloma and HPV-associated cervical/head & neck cancer contexts.
Xenograft and syngeneic ovarian tumor models with tumor burden reduction and survival benefit.
Exploration of the RA compound class for solid cancers is motivated by the described K48-linked substrate-selective effects and RA375 performance.
Treatment of orthotopic human ovarian cancer xenografts is associated with reduced tumor burden and increased survival.
Evaluation of compounds 1-57 by IC50 values against HeLa and SKOV3 cells is documented.
Treatment of cancer selected from the specified group of cancer types, including a cancer associated with Human Papilloma Virus (HPV), with explicitly listed types including breast cancer, cervical cancer, ovarian cancer, multiple myeloma, and pancreatic cancer.
Interested in licensing this patent?