Pyrazolo-quinolines as Selective Inhibitors of Genotoxic Stress-Induced Ikk/nf- Kb Pathways for Cancer Therapy

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The invention discloses a new class of chemical compounds—pyrazolo-quinolines—that act as highly selective inhibitors of the genotoxic stress-induced IKK/NF-κB signaling pathway, primarily for cancer therapy. These compounds specifically target and inhibit the cdc-like kinases CLK2 and CLK4, which are newly identified as essential regulators in the activation of NF-κB following DNA damage (such as that caused by chemotherapy or radiation). The targeted inhibition makes tumor cells more sensitive to DNA-damaging treatments by blocking their pro-survival and anti-apoptotic signaling, potentially overcoming therapy resistance with limited side effects compared to previous NF-κB/IKK inhibitors.

Use CasesContent extracted from patent full text and abstract with AI.

• Treatment of various types of cancers, especially those exhibiting resistance to chemotherapy or radiotherapy due to genotoxic stress-induced NF-κB activation.
• Use as an adjunct (add-on) therapy alongside DNA-damaging agents such as etoposide, cisplatin, or radiation to increase cancer cell apoptosis and improve treatment efficacy.
• Treatment of cancers associated with defective DNA repair mechanisms (for example, BRCA1/2-mutant cancers) and genomic instability.
• Use in preclinical in vitro studies to investigate and modulate DNA damage-induced NF-κB signaling pathways.
• Potential for development into pharmaceutical compositions for both human and veterinary cancer therapies.

BenefitsContent extracted from patent full text and abstract with AI.

• Pathway-selective inhibition: The compounds specifically inhibit only genotoxic stress-induced IKK/NF-κB activation, sparing other physiological NF-κB functions and reducing unwanted side effects such as immunosuppression.
• Overcomes therapy resistance: By blocking the tumor's anti-apoptotic signaling after DNA damage, these inhibitors sensitize cancer cells to standard chemotherapy and radiation, potentially reversing treatment resistance.
• Improved safety profile: Unlike previous broad-spectrum NF-κB/IKK inhibitors, these compounds have a low risk of severe adverse effects due to their targeted mechanism.
• Broad cancer applicability: Applicable to a wide variety of solid tumors and hematological malignancies where genotoxic stress-induced NF-κB plays a role, including breast, ovarian, gastric, and hematological cancers.
• Facilitates combination therapies: Can be combined with DNA damage-inducing therapies to achieve greater tumor cell death and reduce required doses of standard cytotoxic drugs, potentially minimizing toxicity.
• Novel mechanism: Targets CLK2 and CLK4, kinases not previously implicated in NF-κB regulation, offering a new therapeutic modality for cancer.
• Pharmaceutical flexibility: The compounds can be formulated in various dosages and delivery methods, and can be co-administered with other anticancer therapies.

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Patent Abstract

The invention relates to chemical compounds and their use in the treatment of a cancer exhibiting genotoxic stress-induced IKK/NF-κB activation. The invention relates to chemical compounds useful for inhibiting genotoxic stress-induced IKK/NF-κB activation. The invention further relates to a pharmaceutical composition comprising a compound of the invention for the treatment of a subject afflicted by a cancer exhibiting genotoxic stress-induced IKK/NF-κB activation. The invention further relates to an in vitro method for the inhibition of genotoxic stress-induced NF-kB signaling or inhibition of DNA repair mechanisms.