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Publication Number
US-12435030-B2
Publication Date
2025-10-07
Expiration Date
Abstract
Described herein, inter alia, are compositions of PCNA modulators and methods for treating or preventing cancer.
Core Innovation
The invention relates to pharmaceutical compositions comprising a compound having a defined formula, together with an anti-cancer agent and a pharmaceutically acceptable excipient, or a pharmaceutically acceptable salt thereof. The compound is characterized by Ring A and Ring B selections and variable substituent groups including R1, R2, R3, R7, R8, R9, and R10, with defined integer parameters z1, m1, v1, and n1 and halogen options X1, X2, X3, and XA.
Additional embodiments expand the compound definitions with R4, R5, R11-R14, and R15-R18, together with z2, z3, m4/m5/v4/v5, n4/n5, and X4/X5/XB/XC. The invention relates to PCNA modulators for cancer treatment and to compositions and treatment approaches targeting diseases associated with PCNA activity. The described mechanism centers on PCNA inhibition by contacting PCNA with an effective amount of the defined compound(s).
The partial content links this to inhibition of PCNA activity, DNA replication, and homologous recombination repair, together with binding competition with T3, binding to the interdomain connecting loop or L126-Y133 loop region of PCNA, and preference for acidic caPCNA over basic nmPCNA. The disclosed embodiments include compound structures such as AOH1160 and AOH1996 and frame the therapeutic concept around anti-cancer activity.
The patent context describes selective neuroblastoma killing, cisplatin sensitization, cell-cycle arrest, apoptosis, DNA damage, and in vivo tumor growth suppression, and it identifies cancer-treatment contexts including neuroblastoma and brain cancer. The compositions are positioned for use with anti-cancer agents such as platinum-based compounds, including cisplatin.
Claims Coverage
The consolidated claim coverage centers on one independent pharmaceutical composition claim, with dependent refinements across the input items. The independent coverage combines a defined PCNA modulator compound scaffold with a pharmaceutically acceptable excipient and an anti-cancer agent class list, while dependent material further narrows Ring B, substituent choices, and treatment context; overall, three inventive features are consistently represented.
Pharmaceutical composition with defined compound formula and anti-cancer agent
A pharmaceutical composition comprising a compound having a defined formula, a pharmaceutically acceptable excipient, and an anti-cancer agent selected from platinum-based compounds, topoisomerase inhibitors, EGFR inhibitors, ras inhibitors, MEK inhibitors, signal transduction inhibitors, or signal transduction modulators, with the compound provided as the compound formula or a pharmaceutically acceptable salt thereof.
Ring A and Ring B selection within the compound formula
Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl, and Ring B is substituted or unsubstituted 1-naphthyl or substituted or unsubstituted isoquinolinyl.
Substituent and parameter constraints on the compound formula
R1, R2, R3, and R7, R8, R9, and R10 are defined by the stated functional-group and ring options, with z1 an integer from 0 to 4, m1 and v1 independently 1 or 2, n1 independently an integer from 0 to 4, and X1, X2, X3, and XA independently Cl, Br, I, or F.
The claim coverage is directed to a pharmaceutical composition containing a PCNA-targeting compound defined by Ring A and Ring B selections plus extensive substituent and integer/halogen constraints, combined with a pharmaceutically acceptable excipient and an anti-cancer agent restricted to the recited therapeutic classes. Dependent refinements in the input further specify Ring B as 1-naphthyl, refine substituent choices, and include treatment-context additions such as radiation.
Stated Advantages
Selective neuroblastoma killing.
Replication and homologous recombination inhibition.
Inhibition of DNA replication and homologous recombination repair associated with DNA damage.
Cell-cycle arrest.
Apoptosis.
Cisplatin sensitization.
In vivo tumor growth suppression.
Inhibits PCNA activity by contacting PCNA.
Documented Applications
Cancer treatment.
Treating PCNA-associated disease and cancer, including neuroblastoma and brain cancer.
Inhibiting PCNA activity by contacting PCNA.
Neuroblastoma context, including selective killing of neuroblastoma.
Combination context with cisplatin.
Cancer types explicitly listed in the provided context: triple negative breast cancer, leukemia, lung cancer, colon cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
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