Disclosed herein are compounds that form covalent bonds with Bruton's tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. Methods for the preparation of the compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Inhibitors of bruton's tyrosine kinase

Translation and protein synthesis: macrolides.

Disclosed herein are methods for treating a cancer comprising: a. administering a Btk inhibitor to a subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; b. determining the expression profile of one or more biomarkers from one or more subpopulation of lymphocytes; and c. administering a second agent based on the determined expression profile.

Use of inhibitors of bruton's tyrosine kinase (Btk)

Engineered Biosynthesis of Geldanamycin Analogs for Hsp90 Inhibition

The present application relates to compounds having the inhibitory activity to apoptosis signal-regulating kinase (ASK1), thus are thus useful in treating ASK1-mediated conditions, including autoimmune disorders, inflammatory diseases, cardiovascular diseases, diabetes, diabetic nephropathy, cardio-renal diseases, including kidney disease, fibrotic diseases, respiratory diseases, COPD, idiopathic pulmonary fibrosis, acute lung injury, acute and chronic liver diseases, and neurodegenerative diseases.

Apoptosis signal-regulating kinase inhibitors

Resorcylic acid lactones having a C5-C6 cis double bond and a ketone at C7 and other compounds capable of Michael adduct formation are potent and stable inhibitors of a subset of protein kinases having a specific cysteine residue in the ATP binding site.

Specific kinase inhibitors

The invention relates to recombinant polyketide synthase enzymes, polyketide modifying proteins, and other proteins involved in polyketide biosynthesis or function. The invention provides domains of geldanamycin and herbimycin polyketide synthases, polynucleotides that encode such enzymes, and to host cells in which such encoding polynucleotides can be advantageously expressed.

Recombinant polynucleotides encoding pro-geldanamycin producing polyketide synthases and accessory proteins, and uses thereof

Erythromycin biosynthesis is mediated by a modular polyketide synthase (PKS).1,2) Such PKSs feature a separate enzyme active site, as part of discrete protein domains for each biosynthetic step catalyzed, making them ideal targets for directed biosynthesis. Alteration or replacement of individual domains or modules has allowed many new polyketides to be generated with modifications at positions not readily accessible by synthetic organic chemistry.3,4) As a starting material for the synthesis of new erythromycin analogues, we set out to generate 6-demethylerythromycins by directed biosynthesis. The 6-methyl group of erythromycin is derived from incorporation of a methylmalonyl unit by the acyltransferase in module 4 (AT4) of the 6-deoxyerythronolide B synthase (DEBS) PKS.5) Recently, REEVES and co-workers6) successfully altered the substrate specificity of AT4 in DEBS through site-specific mutagenesis to accept malonyl-CoA or methylmalonyl-CoA. The modified DEBS genes were expressed in the heterologous host Streptomyces lividans, and consequently, the aglycone 6-demethyl-6deoxyerythronolide B was produced. RODRIGUEZ et al.7) described a novel gene delivery and expression system that allows the rapid engineering of recombinant PKSs in an erythromycin overproducing strain of Saccharopolyspora erythraea K24-1. Here, we report the use of that gene delivery system to introduce the DEBS genes harboring a mutagenized AT4 domain into S. erythraea K24-1 to produce 6-demethyl erythromycins. Compound 1 (7-hydroxy-6-demethyl-6-deoxy erythromycin D) was produced, which is demethylated at the 6-position as predicted, but unexpectedly has a hydroxyl group at the 7-position rather than at the 6-position. In order to express the AT4-modified DEBS in S. erythraea K24-1, the genes encoding the engineered PKS (mutation 3 in reference 6) were transferred from the S. lividans expression vector to the pSET 152 integrating vector under control of the native eryAp promoter.7) The resulting vector pKOS159-42 was introduced into S. erythraea K24-1 by conjugation and the culture broths of the antibiotic-producing isolates were screened by LC/MS for the presence of compounds with mass spectra consistent with 6-demethyl-erythromycin analogues. One isolate was selected for scale-up in 10-liter bioreactors, which produced high levels of a compound with m/z 690 consistent with the mass of 6-demethyl-erythromycin D. Each production bioreactor containing 9 liters of production medium was inoculated with 500ml of an actively growing culture of S. erythrea K24-1::pKOS159-

Isolation and Characterization of 7-Hydroxy-6-demethyl-6-deoxy-erythromycin D, a New Erythromycin Analogue, from Engineered Saccharopolyspora erythraea

L'invention concerne des lactones d'acide resorcyclique comportant une double liaison en position C5-C6 cis et une cetone en C7, ainsi que d'autres composes pouvant former un produit d'addition de Michael, qui constituent des inhibiteurs puissants et stables d'un sous-groupe de proteines kinases comportant un residu cysteine specifique au niveau de leur site de liaison ATP.

Inhibiteurs de kinases specifiques

Isolation and Characterization of 7‐Hydroxy‐6‐demethyl‐6‐deoxy‐erythromycin D, a New Erythromycin Analogue, from Engineered Saccharopolyspora erythraea.

Richard C. Hutchinson

Papers

Specific kinase inhibitors

Recombinant polynucleotides encoding pro-geldanamycin producing polyketide synthases and accessory proteins, and uses thereof

Isolation and Characterization of 7-Hydroxy-6-demethyl-6-deoxy-erythromycin D, a New Erythromycin Analogue, from Engineered Saccharopolyspora erythraea

Inhibiteurs de kinases specifiques

Isolation and Characterization of 7‐Hydroxy‐6‐demethyl‐6‐deoxy‐erythromycin D, a New Erythromycin Analogue, from Engineered Saccharopolyspora erythraea.