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Biotech / Medical : Kosan BioSciences -- KOSN -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (617)	10/11/2005 11:39:14 PM
From: tuck	Respond to of 933

[17AAG versus AML with mutated KIT] >>Leuk Res. 2005 Oct 4; [Epub ahead of print] The Hsp90 inhibitor 17-allylamide-17-demethoxygeldanamycin induces apoptosis and differentiation of Kasumi-1 harboring the Asn822Lys KIT mutation and down-regulates KIT protein level. Yu W, Rao Q, Wang M, Tian Z, Lin D, Liu X, Wang J. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China; Department of Clinical Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, PR China. Heat shock protein 90 (Hsp90) serves as a chaperone for a number of cell signaling proteins, including many tyrosine and serine/threonine kinases, which are involved in proliferation and/or survival. The benzoquinone ansamycin geldanamycin has been shown to bind to Hsp90 and to specifically inhibit this chaperone's function, resulting in client protein destabilization. 17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a chemical derivative of geldanamycin. KIT is the receptor for stem cell factor (SCF) and required for normal hematopoiesis. Mutations in c-Kit result in ligand-independent tyrosine kinase activity and uncontrolled cell proliferation. Kasumi-1 is t(8;21) acute myeloid leukemia (AML) cell line harboring mutated KIT with Asn822Lys substitution. Our present studies demonstrate that 17-AAG inhibits Kasumi-1 cells proliferation and exerts apoptosis- and differentiation-inducing effects in a dose- and time-dependent manner. The growth-inhibitory IC50 value for 17-AAG treatment is 0.62mumol/L. Characteristic apoptotic features were confirmed by morphology, internucleosomal DNA fragmentation, and annexin V staining. 17-AAG also causes the G0/G1 block of Kasumi-1 cells. Significantly, 17-AAG-induced apoptosis of Kasumi-1 cells is associated with a decline in KIT protein level. Our findings strongly suggest that 17-AAG might be an effective therapeutic agent targeting AML cells harboring mutated KIT.<< I'll have to dig to see how big a proportion of the AML this would target. Here's a start: >>Haematologica. 2004 Aug;89(8):920-5. KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication. Beghini A, Ripamonti CB, Cairoli R, Cazzaniga G, Colapietro P, Elice F, Nadali G, Grillo G, Haas OA, Biondi A, Morra E, Larizza L. Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Italy. BACKGROUND AND OBJECTIVES: Mutations of KIT receptor tyrosine kinase are involved in the constitutive activation and development of human hematologic malignancies. Gain-of-function mutations in the second intracellular kinase domain (TK2) and in the juxtamembrane domain are described in patients with core binding factor acute myeloid leukemia (CBFL) and are associated with leukocytosis. We evaluated the incidence of KIT mutation in 52 adult patients with de novo CBFL and in 49 FLT3/ITD-negative childhood patients with de novo acute myeloid leukemia (AML), excluding cases of acute promyelocytic leukemia. DESIGN AND METHODS: In order to analyze the role of KIT in CBFL we examined the KIT mutations in 52 adult CBFL, including 15 previously reported patients, and in 49 non-APL childhood AML patients using sensitive detection methods. We correlated our findings with the presence of trisomy 4 and investigated the relationship of the extra chromosome 4 with KIT mutations. RESULTS: Several kinds of gain-of-function KIT mutations were found in 24 of the 52 (46.1%) adult CBFL cases and 6 of the 49 (12.2%) non-APL childhood AML patients. KIT mutations were detected in 4 of the 8 adult patients and one childhood AML case bearing trisomy of chromosome 4 as either the sole cytogenetic aberration or a karyotypic aberration additional to t(8;21). In three of the trisomy 4 cases we demonstrated that trisomy 4 leads to duplication of the KIT mutated allele. INTERPRETATION AND CONCLUSIONS: These results underline that the KIT gene is activated in AML characterized by distinct cytogenetic and molecular genetic patterns and represents the most frequently mutated target in adult CBFL.<< Cheers, Tuck

To: tuck who wrote (617)	1/18/2006 3:58:04 PM
From: tuck	Read Replies (1) \| Respond to of 933

[23,24-dihydrodiscodermolide analogues with simplified lactone regions] >>Bioorg Med Chem Lett. 2006 Jan 11; [Epub ahead of print] A series of 23,24-dihydrodiscodermolide analogues with simplified lactone regions. Shaw SJ, Sundermann KF, Burlingame MA, Zhang D, Petryka J, Myles DC. Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. A collection of seven new 23,24-dihydrodiscodermolide analogues have been synthesized with modifications to the lactone ring, some of which show antiproliferative activities similar to discodermolide.<< Still another way of modifying discodermolides. It'll be interesting to see what they settle on. Kind of neat to watch the search from the beginning like this. AB Smith, who worked on the studies to which this post links, has his own little web site. One looks for a way to attach value and IP to a natural product, I guess. This one is from a marine sponge . . . absmithgroup.info Cheers, Tuck