The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.

Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have been identified herein in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFC). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant ALK kinase polypeptides, probes for detecting it, isolated mutant polypeptides, recombinant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The disclosed identification of this new fusion protein enables methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

The invention provides to PKN1 gene fusions, PKN1 fusion proteins, and fragments of those genes and polypeptides. The invention further provides methods of diagnosing and treating diseases or disorders associated with PKN1 fusions, such as conditions mediated by aberrant PKN1 expression or activity, or over expression of PKN1.

The present invention concerns the field of diagnostics. Specifically, it relates to a method for assessing a subject with suspected infection comprising the steps of determining the amount of a first biomarker in a sample of the subject, said first biomarker being sFlt1, determining the amount of a second biomarker in a sample of the subject, wherein said second biomarker is selected from the group consisting of: Cystatin C, IGFBP7, a cardiac Troponin, Creatinine, STREM1, PCT and Bilirubin, comparing the amounts of the biomarkers to references for said biomarkers and/or calculating a score for assessing the subject with suspected infection based on the amounts of the biomarkers, and assessing said subject based on the comparison and/or the calculation. The invention also relates to the use of a first biomarker being sFltl and a second biomarker selected from the group consisting of: Cystatin C, IGFBP7, a cardiac Troponin, Creatinine, sTREM1, PCT and Bilirubin, or a detection agent specifically binding to said first biomarker and a detection agent specifically binding to said second biomarker for assessing a subject with suspected infection. Moreover, the invention further relates to a computer-implemented method for assessing a subject with suspected infection and a device and a kit for assessing a subject with suspected infection.

The present invention relates to a method for assessing a subject with suspected infection comprising the steps of determining the amount of a first biomarker in a sample of the subject, said first biomarker being GDF-15, determining the amount of a second biomarker in a sample of the subject, wherein said second biomarker is selected from the group consisting of: sFLT1, Cystatin C, IGFBP-7, Bilirubin, ESM-1, sTREM-1, Procalcitonin, cardiac Troponin, BNP-type peptide, Alanine aminotransferase, and Aspartate aminotransferase, comparing the amounts of the biomarkers to references for said biomarkers and/or calculating a score for assessing the subject with suspected infection based on the amounts of the biomarkers, and assessing said subject based on the comparison and/or the calculation. The invention also relates to the use of a first biomarker being GDF-15 and a second biomarker selected from the group consisting of sFLT1, Cystatin C, IGFBP-7, Bilirubin, ESM-1, sTREM-1, Procalcitonin, cardiac Troponin, BNP-type peptide, Alanine aminotransferase, and Aspartate aminotransferase or a detection agent specifically binding to said first biomarker and a detection agent specifically binding to said second biomarker for assessing a subject with suspected infection. Moreover, the invention further relates to a computer-implemented method for assessing a subject with suspected infection and a device and a kit for assessing a subject with suspected infection.

Novel gene deletions and translocations involving chromosome 2 resulting in fusion proteins combining part of Anaplastic Lymphoma Kinase (ALK) kinase with part of a secondary protein have now been identified in human solid tumors, e.g. non-small cell lung carcinoma (NSCLC). Secondary proteins include Echinoderm Microtubule-Associated Protein-Like 4 (EML-4) and TRK-Fusion Gene (TFG). The EML4-ALK fusion protein, which retains ALK tyrosine kinase activity, was confirmed to drive the proliferation and survival of NSCLC characterized by this mutation. The invention therefore provides, in part, isolated polynucleotides and vectors encoding the disclosed mutant polypeptides, probes for detecting it, isolated mutant polypeptides, and reagents for detecting the fusion and truncated polypeptides. The invention also provides methods for determining the presence of these mutant polypeptides in a biological sample, methods for screening for compounds that inhibit the proteins, and methods for inhibiting the progression of a cancer characterized by the mutant polynucleotides or polypeptides.

The invention relates to inhibitors of CDK12 (cyclin-dependent kinase 12), and there use in the treatment or prevention of a disorder in a subject caused by the generation of repeat expansion transcripts.

The present invention relates to cyclin-dependent kinase, 12, CDK12 (cyclin-dependent kinase 12), for use as a marker for DNA damage in proximity of transcribed genomic loci in a sample, and to methods for identifying and/or quantifying in a sample DNA damage events associated to actively transcribed genomic loci, comprising detecting the CDK12 protein in proximity of the aforesaid genomic loci.

Provided is a method for measuring tyrosine phosphatase and tyrosine kinase activity, as a high-sensitivity measuring method, which is suitable for high throughput and which uses a compound represented by general formula (I) (in the formula, A represents a conjugated ring; L represents a linker or the like having a labeling substance at an end; R.sup.1 represents a hydrogen atom or the like; and R.sup.2 and R.sup.3 each represent a hydrogen atom, an alkyl group or the like).

Certain imidazopyrazines of Formula I and pharmaceutical compositions thereof are provided herein: ##STR00001##
Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of Syk activity, which comprises administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are provided. Also provided are methods for determining the presence or absence of Syk kinase in a sample.