This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

This invention is related to the field of PCSK9 biology and the composition and methods of use of small molecule ligands for modulation of PCSK9 biological activity. In particular, the invention provides compositions of small molecule compounds that modulate circulating levels of low density lipoproteins by altering the conformation of the protein PCSK9. Binding these small molecule ligands to PCSK9 alters the conformation of the protein, modifying the interaction between PCSK9 and an endogenous low density lipoprotein receptor, and can lead to reduced or increased levels of circulating LDL-cholesterol. High LDL-cholesterol levels are associated with increased risk for heart disease. Low LDL-cholesterol levels may be problematic in other conditions, such as liver dysfunction; thus, there is also utility for small molecule ligands that can raise LDL levels.

Applicants have developed an amplification system and methodology for IHC and ISH staining that utilizes “click chemistry” to covalently bind reporter molecules to tissue.

Applicants have developed an amplification system and methodology for IHC and ISH staining that utilizes “click chemistry” to covalently bind reporter molecules to tissue.

The present invention relates to the phosphohistidine analogs of the present invention which of the formula ##STR00001##
and the hapten containing the residue of same. It also relates to the hapten conjugated to a carrier molecule and the isolated antibodies raised against the immunogens, said antibodies recognizing polypeptide containing a phosphorylated histidine or the phosphotriazole residue but it does not recognize an amino acid or polypeptide that is not phosphorylated or a polypeptide which is phosphorylated on amino acids other than histidine but not on histidine.

The present invention relates to the phosphohistidine analogs of the present invention which of the formula ##STR00001##
and the hapten containing the residue of same. It also relates to the hapten conjugated to a carrier molecule and the isolated antibodies raised against the immunogens, said antibodies recognizing polypeptide containing a phosphorylated histidine or the phosphotriazole residue but it does not recognize an amino acid or polypeptide that is not phosphorylated or a polypeptide which is phosphorylated on amino acids other than histidine but not on histidine.

Disclosed herein are novel quinone methide analog precursors and embodiments of a method and a kit of using the same for detecting one or more targets in a biological sample. The method of detection comprises contacting the sample with a detection probe, then contacting the sample with a labeling conjugate that comprises an enzyme. The enzyme interacts with a quinone methide analog precursor comprising a detectable label, forming a reactive quinone methide analog, which binds to the biological sample proximally to or directly on the target. The detectable label is then detected. In some embodiments, multiple targets can be detected by multiple quinone methide analog precursors interacting with different enzymes without the need for an enzyme deactivation step.

Disclosed herein are novel quinone methide analog precursors and embodiments of a method and a kit of using the same for detecting one or more targets in a biological sample. The method of detection comprises contacting the sample with a detection probe, then contacting the sample with a labeling conjugate that comprises an enzyme. The enzyme interacts with a quinone methide analog precursor comprising a detectable label, forming a reactive quinone methide analog, which binds to the biological sample proximally to or directly on the target. The detectable label is then detected. In some embodiments, multiple targets can be detected by multiple quinone methide analog precursors interacting with different enzymes without the need for an enzyme deactivation step.

Disclosed herein are inhibitors of the GGDPS enzyme, and methods for their use in treating or preventing diseases, such as multiple myeloma. The inhibitors described herein can include compounds of Formula (I) and pharmaceutically acceptable salts thereof:

##STR00001##

wherein the substituents are described.

Disclosed herein are inhibitors of the GGDPS enzyme, and methods for their use in treating or preventing diseases, such as multiple myeloma. The inhibitors described herein can include compounds of Formula (I) and pharmaceutically acceptable salts thereof:

##STR00001##

wherein the substituents are described.