A NOVEL INTERACTION SITE ON PRO-APOPTOTIC BAX AS A TARGET FOR PHARMACOLOGIC MODULATION OF CELL SURVIVAL AND APOPTOSIS
Cancer, Autoimmune Disease, Diabetes, Neurodegenerative Disease, Heart Attack, Stroke
Methods, kits and compositions for modulating the activity of BCL-2 family polypeptides (e.g., BAX) by targeting a new regulatory site on BCL-2 family proteins. Agonists and antagonists to this site will be potentially used in the variety of diseases characterized by excessive cell proliferation or death including those disorders characterized by the deregulation of one or more polypeptides of the BCL-2 family.
Activation of the pro-apoptotic BCL-2 family member BAX is an essential gateway to mitochondrial dysfunction and programmed cell death for a variety of stress stimuli. The explicit trigger mechanism responsible for converting the quiescent form of BAX into an activated killer protein is unknown. Using specific stabilized peptides of BAX activating molecule, BIM, which directly initiates BAX-mediated mitochondrial apoptosis, DFCI scientists discovered and characterized a novel BAX interaction site that is distinct from the canonical binding groove known for anti-apoptotic proteins. This activation site establishes a new target for therapeutic modulation of apoptosis.
Inventor: WALENSKY, Loren, D. | TJANDRA, Nico | GAVATHIOTIS, Evripidis | SUZUKI, Motoshi | BIRD, Gregory, H.
Priority Number: WO2009042237A3
IPC Current: G01N003300 | G01N003350
Assignee Applicant: Dana-Farber Cancer Institute Inc. | National Institutes of Health
Title: METHODS AND COMPOSITIONS FOR MODULATING BCL-2 FAMILY POLYPEPTIDES | PROCÉDÉS ET COMPOSITIONS POUR MODULER DES POLYPEPTIDES DE LA FAMILLE BCL-2
Usefulness: METHODS AND COMPOSITIONS FOR MODULATING BCL-2 FAMILY POLYPEPTIDES | PROCÉDÉS ET COMPOSITIONS POUR MODULER DES POLYPEPTIDES DE LA FAMILLE BCL-2
Summary: The method is useful for treating disorder of aberrant cellular proliferation or apoptotic blockade, where the disorder is cancer comprising solid tumor, leukemia, lymphoma, chemoresistant cancer (which is resistant to ABT-737 or ABT-263.), and an autoimmune disease. The method is useful for treating a tumor (all claimed), where the tumor is e.g. stromal tumors (fibroadenoma), phyllodes tumor, and sarcomas, and epithelial tumors (large duct papilloma). The method is useful e.g. for treating or preventing a disorder of deregulated apoptosis (hyperpoliferative disorder) in an individual, and cellular proliferative and/or differentiative disorders of: breast (proliferative breast disease (epithelial hyperplasia and sclerosing adenosis) and male breast (gynecomastia and carcinoma)); lung (bronchogenic carcinoma (paraneoplastic syndromes and metastatic tumors)); pathologies of the pleura (noninflammatory pleural effusions); liver (hyperplasias, adenomas and malignant tumors); and ovary (ovarian tumors such as, tumors of coelomic epithelium and serous tumors). The compound is useful to treat/ prevent e.g. ischemia, hypocellular/hypoplastic, acellular/aplastic, or hypercellular/hyperplastic conditions, hematologic disorders (e.g. fanconi's anemia, aplastic anemia, thalaessemia and myelodysplasia), neurologic disorders, Alzheimer's disease, Down's Syndrome, idiopathic myeloma, macroglobulinemia-associated myeloma, familial amyloid polyneuropathy, adult onset diabetes, insulinoma, familial amyloidotic polyneuropathy, scrapie, Creutzfeldt-Jacob Disease, Gerstmann Straussler-Scheinker Syndrome, bovine spongiform encephalitis, a prion-mediated disease, Huntington's disease, cardiovascular disorders (e.g. inflammatory disorders), atherosclerosis, myocardial infarction, stroke, thrombosis, aneurism, heart failure, ischemic heart disease, angina pectoris, sudden cardiac death, hypertensive heart disease; non-coronary vessel disease such as small vessel disease, nephropathy, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, xanthomatosis, asthma, hypertension, emphysema and chronic pulmonary disease. Tests details are described but no results given.
Novelty: Identifying new or known compounds e.g. bis-indole maleimide polypeptide, which modulates the activity of a B-cell lymphoma-2 family polypeptide, comprises contacting the family polypeptide with the compound; and detecting the activity
Disease Diagnostic/Treatment
Cancer/Tumor
USA
