Peptidomimetic inhibitors of PSMA, compounds comprising them, and methods of use
Inventors
Assignees
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Publication Number
US-8293725-B2
Publication Date
2012-10-23
Expiration Date
Abstract
Compounds of the formula, A-L-B, wherein A is glutamate or a glutamate analog; L is a phosphoramidate or a phosphoramidate analog; and B is serine or a serine analog are described which are potent inhibitors of prostate-specific membrane antigen (PMSA). Such compounds are useful in treatment of prostate cancer; and when chemically attached to a fluorescent dye, can efficiently and selectively label prostate cancer cells for fluorescent imaging.
Core Innovation
The invention relates to contacting PSMA-presenting cells with a compound of a defined formula in which the composition includes phosphorus-containing phosphoramidate and phosphoryl motif groups and variable substituents defined by R1, R2, R3, R4, L, M, T, L1, and L2, together with a moiety R8. The moiety R8 functions either as a detectable label or as a biomolecular anchor linked to a solid support, depending on whether the method is directed to detecting or capturing PSMA-presenting cells.
The method includes detecting the detectable label under conditions that permit detection of only PSMA-presenting cells, or capturing the PSMA-presenting cells when R8 is a biomolecular anchor linked to a solid support. The disclosure also provides broad molecular definitions for glutamate/serine analogs and fluorescein/fluorescein derivatives, together with example compounds including LW-39-5FAMX, LW-54-F5EX, TL-LW-54-BnDTPA, TL-LW-54-LC-Biotin, and steroid/cholesteryl-phosphoryl analogs.
The disclosure further describes PSMA inhibition, time-dependent and irreversible inhibition, covalent PSMA homodimer formation, specificity versus MMP-9, and inhibitor-directed labeling and fluorescence microscopy using fluorescent conjugates.
Claims Coverage
The partial content includes one independent claim directed to a method for capturing and/or detecting PSMA-presenting cells. The independent claim is supported by dependent claims that specify what R8 is and narrow the downstream detection or capture workflow.
Contacting PSMA-presenting cells with a compound of a defined formula
A method for capturing and/or detecting PSMA-presenting cells comprising contacting the cells with a compound of the formula wherein the phosphorus-containing groups and variable substituents are defined as specified.
Using R8 as either a detectable label or a biomolecular anchor linked to a solid support
The method wherein R8 is a detectable label or a biomolecular anchor linked to a solid support, with detection performed when R8 is a detectable label and capture performed when R8 is the biomolecular anchor linked to a solid support.
Detecting only PSMA-presenting cells or capturing PSMA-presenting cells
When R8 is a detectable label, detecting the detectable label under conditions that permit detection of only PSMA-presenting cells; and when R8 is a biomolecular anchor linked to a solid support, capturing the PSMA-presenting cells.
Overall, the claim coverage centers on a PSMA-targeting phosphoramidate/phosphoryl compound defined by a detailed formula, combined with an R8 moiety that enables either label-based detection restricted to PSMA-presenting cells or solid-support anchored capture of PSMA-presenting cells.
Stated Advantages
Stated high affinity and specificity, including low IC50 values.
Stated improved labeling/capture efficiency.
Stated cost/efficiency of small-molecule preparation compared with antibody-based PSMA targeting.
Documented Applications
Selective fluorescent imaging using fluorescent dye-functionalized PSMA/PMSA inhibitors.
Imaging using chelators for radioisotopes and MRI contrast.
Capture assays using binding-pair components linked to the inhibitor conjugates.
Therapeutic use of PSMA/PMSA inhibitor conjugates carrying therapeutic agents and optionally radiocytotoxic isotopes.
Chimeric conjugate use cases including conjugates attached to detectable labels, therapeutic agents, or solid supports.
Detecting PSMA-presenting cells using inhibitor-directed labeling and fluorescence microscopy with fluorescent conjugates.
Specificity assessment versus MMP-9 in the context of PSMA inhibition, including time-dependent and irreversible inhibition and covalent PSMA homodimer formation.
Capturing PSMA-presenting cells using a solid support with an R8 biomolecular anchor, with subsequent release and fluorescent-label detection by flow cytometry.
Detecting via plasmon resonance.
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