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-9925269-B2
Publication Date
2018-03-27
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 describes a therapeutic compound having a defined A-B-D structure. Component A is selected from compounds of formula (I), formula (II), formula (III), or combinations thereof, with W selected from an aryl, a C1-C6 alkyl, an alkenyl, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C3-C6 heterocycloalkyl, R being H or an alkyl, and m being an integer from 12 to 24.
Component B is selected as a bond or a linker compound of formula (IV), defined by a Y-(CH2)n-Z connection where Y is selected from bond, O, NH, C(O), NHSO2O, and OC(O)O, and Z is selected from O, NH, C(O), C(O)O, C(O)NH, SO2, and OC(O)OCH2, with n being an integer from 0 to 6. The disclosed framework supports conjugates that connect the CLR1404 core to anti-cancer drugs through specified linker chemistries.
Component D is selected from an anti-cancer drug, including paclitaxel, irinotecan, topotecan, gemcitabine, cisplatin, geldanamycin, and mertansine. The disclosed compounds are described as sequestered or retained by cancer cells, providing selective uptake or retention versus healthy tissue.
The scope includes cancer treatment methods, including treatment of cancers comprising cancer stem cells and recurrent cancers, and pharmaceutical compositions comprising the therapeutic compounds and pharmaceutically acceptable carriers. The disclosed A-B-D conjugates are also described in the context of brain tumors and a potential blood-brain barrier crossing.
Claims Coverage
The independent claims center on a structurally defined A-B-D therapeutic compound. The inventive features include constrained selections for A, B, and D, and an additional claim subset defined by structural variables such as n and X.
Formula A-B-D therapeutic compound with constrained A, B, and D
A therapeutic compound comprising formula A-B-D, where A is selected from compounds of formula (I), formula (II), formula (III), or combinations thereof with W selected from specified aryl, alkyl, alkenyl, cycloalkyl, or heterocycloalkyl options, R is H or alkyl, and m is an integer from 12 to 24; B is selected from a bond and a linker compound of formula (IV) defined by Y-(CH2)n-Z with Y and Z selected from specified groups and n an integer from 0 to 6; and D is an anti-cancer drug selected from paclitaxel, irinotecan, topotecan, gemcitabine, cisplatin, geldanamycin, and mertansine.
Therapeutic compound defined by integer n and atom X
A therapeutic compound selected from a group of compounds defined by structural variables, where n is an integer from 0 to 6 and X is O or NH.
Claim coverage is centered on a structurally defined A-B-D therapeutic compound that combines a CLR1404-core-derived component A, a bond or specifically defined linker B, and an anti-cancer drug D from a defined list, with an additional claim subset limited by n and X.
Stated Advantages
Selective sequestration and retention in lipid rafts enriched in cancer cells, with lipid raft disruption reducing uptake.
Retention of the CLR1404 core in cells is described as up to 20 days.
Selective uptake or retention versus healthy tissue, based on the stated premise that CLR1404-linked drugs are sequestered or retained by cancer cells.
Targeting cancer cells and cancer stem cells, including cancers such as brain tumors.
Documented Applications
Pharmaceutical compositions comprising the therapeutic compound and one or more pharmaceutically acceptable carriers.
A method of treating cancer that comprises cancer stem cells.
Treatment of recurrent cancers.
Therapeutic targeting in brain tumors, including a potential blood-brain barrier crossing context.
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