DAVID M HOCKENBERY, MD
Osteopathic Medicine at Eastlake Ave, Seattle, WA

2010022, Sep 2, 2010

Mar 9, 2009

12/400717

David M. Hockenbery - Seattle WA, US
Michael K. Manion - Seattle WA, US

Fred Hutchinson Cancer Research Center - Seattle WA

C12Q 1/68, G01N 33/574

435 6, 435 721

The present invention provides methods and combinations of methods for identifying agents that modulate the apoptotic state of a cell by binding to the hydrophobic groove of a Bcl-2 family member anti-apoptotic protein. In certain embodiments, the methods generally comprise the use of Bcl-2 family member proteins having one or more mutations in the hydrophobic groove that, relative to a corresponding protein lacking the mutation, affect, e.g., binding of desired agents or in vitro antimycin sensitivity without substantially altering tertiary protein structure. In these embodiments, the methods comprise the identification of agents that exhibit reduced binding affinities and/or other biological activities for the mutant proteins relative to the corresponding Bcl-2 family member lacking the mutation. In other embodiments, the methods generally comprise the detection of the ability of an agent to induce increased glucose uptake or lactate production in proportion to the level of expression of an anti-apoptotic Bcl-2 family member protein.

2006018, Aug 24, 2006

Jan 13, 2006

11/331652

David Hockenbery - Seattle WA, US
Michael Manion - Seattle WA, US

Fred Hutchinson Cancer Research Center - Seattle WA

C12Q 1/68, G01N 33/574

435007230, 435006000

The present invention provides methods and combinations of methods for identifying agents that modulate the apoptotic state of a cell by binding to the hydrophobic groove of a Bcl-2 family member anti-apoptotic protein. In certain embodiments, the methods generally comprise the use of Bcl-2 family member proteins having one or more mutations in the hydrophobic groove that, relative to a corresponding protein lacking the mutation, affect, e.g., binding of desired agents or in vitro antimycin sensitivity without substantially altering tertiary protein structure. In these embodiments, the methods comprise the identification of agents that exhibit reduced binding affinities and/or other biological activities for the mutant proteins relative to the corresponding Bcl-2 family member lacking the mutation. In other embodiments, the methods generally comprise the detection of the ability of an agent to induce increased glucose uptake or lactate production in proportion to the level of expression of an anti-apoptotic Bcl-2 family member protein.

2012025, Oct 4, 2012

Apr 2, 2012

13/437795

David HOCKENBERY - Seattle WA, US
Julian SIMON - Seattle WA, US

FRED HUTCHINSON CANCER RESEARCH CENTER - Seattle WA

A61K 31/472, A61K 31/4402, A61K 31/4245, A61K 31/166, A61K 31/165, A61K 31/15, A61K 31/135, A61K 31/12, A61K 31/10, A61K 31/05, C07D 217/22, C07D 215/38, C07D 211/04, C07C 233/65, C07C 251/80, A61K 31/47

514310, 514313, 514352, 514364, 514615, 514617, 514639, 514655, 514689, 514709, 514734, 546143, 546162, 546306, 564149, 564185, 564251

Compounds are described that are useful for treating an apoptosis-associated disease, which are specifically cytotoxic to tumor cells that are overexpressing Bcl-x, and are much less cytotoxic in isogenic cells that are not overexpressing Bcl-x. Also described is a method for treating an apoptosis-associated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an active compound that is specifically cytotoxic to tumor cells that are overexpressing Bcl-x, and are much less cytotoxic in isogenic cells that are not overexpressing Bcl-x. Several scaffolds of active compounds are described.

2005023, Oct 27, 2005

Jan 14, 2005

11/036645

David Hockenbery - Seattle WA, US
Julian Simon - Seattle WA, US

Fred Hutchinson Cancer Research Center - Seattle WA

A61K031/365

514450000, 549267000

Disclosed are 2-methoxy antimycin derivatives or analogs that modulate apoptosis by binding to the hydrophobic groove of a Bcl-2 family member protein (e.g., Bcl-2 or BCl-x). The 2-methoxy antimycin derivatives or analogs are used in disclosed methods for treating apoptosis-associated diseases such as, for example, neoplastic disease (e.g., cancer) or other proliferative diseases associated with the over-expression of a Bcl-2 family member protein.