Phospholipid ether analogs as cancer-targeting drug vehicles
Inventors
Weichert, Jamey P. • PINCHUK, Anatoly • Kozak, Kevin • LONGINO, Marc • Grudzinski, Joseph • Titz, Benjamin • Pak, Chorom • Stehle, Nathan
Assignees
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Publication Number
US-9480754-B2
Publication Date
2016-11-01
Expiration Date
Abstract
The present invention is directed to therapeutic compounds capable of targeting cancer cells and cancer stem cells. The present invention is further directed to compositions comprising these therapeutic compounds and methods of treating cancer comprising administering these therapeutic compounds.
Core Innovation
The invention relates to phospholipid ether (PLE) drug-delivery vehicles and therapeutic compounds based on a CLR1404 core adapted for targeting cancer cells and cancer stem cells. The disclosed approach is based on lipid-raft-mediated uptake and retention and is intended to sequester and retain a cargo in tumors. The invention further states that the CLR1404 core is enabled for brain-crossing for brain cancer therapy.
The disclosure provides therapeutic compound conjugates formed by linking cisplatin, geldanamycin, mertansine, paclitaxel, irinotecan, topotecan, gemcitabine, and CLR1404-related cores through linker structures. The linking strategies include cleavable or non-cleavable linker structures, carbonate, carbamate, amide, ester, amide-ester related linker constructs, and maleimide linker chemistry, with attachment described at specific paclitaxel OH sites including 2′-OH and/or 7-OH.
The document further includes synthesis examples for CLR1404-related conjugates and precursors, including CLR1401 azide/amine and paclitaxel prodrug derivatives, as well as CLR1601, CLR1602, CLR1603, CLR1607, and CLR1608. Biological evaluation examples are described showing cancer-cell sequestration/uptake and tumor imaging/retention using radioiodinated CLR1404 analogs, including 125I-CLR1404 and 124I-CLR1404 analogs in non-small cell lung cancer and other listed cancer models.
Claims Coverage
The relevant independent claim covers a method of treating multiple specified cancers by administering an effective amount of a therapeutic compound of Formula (V) to a subject with cancer. In the provided material, there is 1 independent claim, with dependent refinements that specify additional cancer context and recurrence.
Administering a Formula (V) therapeutic compound for treating specified cancers
A method of treating breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and/or prostate cancer by administering an effective amount of a therapeutic compound of Formula (V) to a subject with cancer.
Targeting cancers comprising cancer stem cells
The method of treating specified cancers includes treatment where the cancer comprises cancer stem cells.
Treating recurrent cancer
The method is for treating a recurrent cancer.
Across the independent and dependent claims provided, the claimed coverage centers on administering an effective amount of a therapeutic compound of Formula (V) for treating specified cancers, with refinements for cancers comprising cancer stem cells and for recurrent cancer.
Stated Advantages
Enables brain-crossing for brain cancer therapy.
Sequesters and retains cargo in tumors.
Targets cancer cells and cancer stem cells.
Documented Applications
Treatment of breast cancer, lung cancer, pancreatic cancer, colorectal cancer, and/or prostate cancer by administering a therapeutic compound of Formula (V) to a subject with cancer.
Treatment of cancers comprising cancer stem cells.
Treatment of recurrent cancer.
Brain cancer therapy, using brain-crossing for delivery to a brain cancer context.
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