The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.

Provided are methods for the identification of mutant kinases that are resistant to inhibition by a kinase inhibitor. In some embodiments, the methods may be used to assess a test compound or kinase inhibitor for the risk of the development of resistance in vivo, e.g., during clinical administration to treat a disease such as a cancer.

The invention provides, inter alia, methods of prognosing the survival of a multiple myeloma patient based levels of TP53RK in multiple myeloma cells of the patient. Also provided are methods of screening for therapeutic agents for treating multiple myeloma based on their ability to decrease TP53RK levels or activity in a patient with multiple myeloma.

In one aspect, the present invention provides a method of selecting or identifying an agent that inhibits a target protein having an active site. In another aspect, the invention provides a method of selecting an agent that inhibits a target protein having an active site for further optimization. In some embodiments, the methods comprise measuring or predicting stability of an induced fit conformation of an agent contacted to an active site of the protein, wherein the agent is selected if the stability of the induced fit conformation of the agent contacted to the active site of the protein is increased relative to a reference stability.

The present disclosure provides, among other things, novel cyclic-GMP-AMP (cGAMP) analogs, mimics, mimetics and variants, and compositions and kits thereof; methods of using the compounds as described herein for treating cancer, and immune disease, disorders, or conditions; methods of using the compounds as described herein for modulating cGAS and STING; and methods of designing or characterizing a cGAS modulator.

The present invention relates to a composition for detecting phosphatase or kinase activity and a method of detecting phosphatase or kinase activity. The kinase or phosphatase activity may be quantitatively measured in real time by using the composition of the present invention.

Provided are SpdE polypeptides and variants and nucleic acids encoding the SpdE polypeptides and variants. Also provided are vectors including one or more nucleic acids encoding a SpdE polypeptide or variant and cells including a nucleic acid encoding the SpdE polypeptide or variant, as well as cells expressing a SpdE polypeptide or variant and compositions including such cells and a pharmaceutically acceptable carrier. Finally, methods of detecting presence and/or amount of one or more amino acids in a sample are provided. The methods include contacting the sample with a SpdE protein, measuring diguanylate cyclase activity of the SpdE protein; and comparing the diguanylate cyclase activity of the SpdE protein to a control. The methods can utilize isolated SpdE protein or a cell expressing a SpdE protein.

In one aspect, the invention is directed to a method of detecting Cowden syndrome (CS) or CS-like syndrome in an individual comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is positive for CS or CS-like syndrome. In another aspect, the invention is directed to a method of determining whether an individual is at risk for developing Cowden syndrome (CS) or CS-like syndrome comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is at risk for developing for CS or CS-like syndrome. In yet another aspect, the invention is directed to an article of manufacture for detecting Cowden syndrome (CS) or Cowden-like syndrome in an individual, comprising one or more agents that detects mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, and instructions for use.

Disclosed are compositions and methods for measuring tyrosine kinase activity.

In certain aspects, the invention provides a method for treating a disease or condition in a subject, the method comprising co-administering to a subject in need thereof a therapeutically effective amount of at least one ULK1-inhibiting pyrimidine, and a therapeutically effective amount of an mTOR inhibitor.