Leland Stanford Junior University

Harvard College

Other

Howard Hughes Medical Institute

Thomas J Wandless

Gerald R Crabtree

Stuart L Schreiber

Peter Belshaw

David M Spencer

Steffan Nicholas Ho

Roger Briesewitz

Laura Anne Banaszynski

Kurt William Vogel

Ling-Chun Chen

Gregory Thomas Ray

Christopher H Contag

Mark A Sellmyer

Lystranne Alysia Maynard

Steven H Thorne

Mari Iwamoto

David Spencer

Rishi Rakhit

Yusaku Miyamae

Kimberly M Bonger

Kryn Stankunas

Steffan N Ho

Disclosed herein are systems, methods, and compositions for rapidly and reversibly destabilizing a target protein in vitro or in vivo, in the presence or absence of a cell-permeable, synthetic molecule or ligand.

PDE5A destabilizing domains

Methods and compositions for the rapid and reversible destabilizing of specific proteins in vivo using cell-permeable, synthetic molecules are described.

Methods for regulating protein function in cells in vivo using synthetic small molecules

Methods and compositions for the rapid and reversible destabilizing of specific proteins using cell-permeable, synthetic molecules are described. Stability-affecting proteins, e.g., derived from FKBP and DHFR proteins are fused to a protein of interest and the presence or absence of the ligand is used to modulate the stability of the fusion protein.

Method for regulating protein function in cells using synthetic small molecules

Disclosed herein are a light-inducible system and method for rapidly and reversibly modulating protein stability and function. This system and method employs conditionally stable protein domains that regulate the degradation of a fusion protein depending upon the presence or absence of a particular light source.

Light-inducible system for regulating protein stability

Method for regulating protein function in cells in vivo using synthetic small molecules

We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells.

Regulated apoptosis

Bifunctional molecules and methods for their use are provided. The subject bifunctional molecules are conjugates of a drug moiety and a pharmacokinetic modulating moiety, where these two moieties are optionally joined by a linking group. The bifunctional molecules are further characterized in that they exhibit at least one modulated pharmacokinetic property upon administration to a host as compared to a free drug control. The subject bifunctional molecules find use in a variety of therapeutic applications.

Synthetic bifunctional molecules containing drug moiety and pharmacokinetic modulating moiety

Targeted bifunctional molecules and methods for their use are provided. The subject targeted bifunctional molecules are conjugates of a drug moiety and a targeting moiety, where these two moieties are optionally joined by a linking group. The bifunctional molecules are further characterized in that they exhibit a modulated biodistribution upon administration to a host as compared to a free drug control. The subject targeted bifunctional molecules find use in a variety of therapeutic applications.

Targeted bifunctional molecules and therapies based thereon

Bifunctional molecules and methods for their use in the production of binary complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. In the subject methods, an effective amount of the bifunctional molecule is administered to the host. The bifunctional molecule binds to the presenter protein to produce a binary complex that exhibits at least one of improved affinity, specificity or selectivity as compared to the corresponding free drug. The subject methods and compositions find use in a variety of therapeutic applications.

Administering bifunctional molecules containing a drug moiety and presenter protein ligand for therapy

Bifunctional inhibitor molecules and methods for their use in the inhibition of protein&#x2014;protein interactions are provided. The subject bifunctional inhibitor molecules are conjugates of a target protein ligand and a blocking protein ligand, where these two moieties are optionally joined by a linking group. In the subject methods, an effective amount of the bifunctional inhibitor molecule is administered to a host in which the inhibition of a protein&#x2014;protein interaction is desired. The bifunctional inhibitor molecule simultaneously binds to its corresponding target and blocking proteins to produce a tripartite complex that inhibits the target protein&#x2014;protein interaction. The subject methods and compositions find use in a variety of applications, including therapeutic applications.

Bifunctional molecules and their use in the disruption of protein-protein interactions

Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins.

Regulated transcription of targeted genes and other biological events

Bifunctional molecules and methods for their use in the production of binary or tripartite complexes in a host are provided. The bifunctional molecule is a conjugate of a drug moiety and a presenter protein ligand. The molecular weight of the bifunctional molecule is less than about 5000 daltons. In the methods, an effective amount of the bifunctional molecule is administered to the host. In certain embodiments the bifunctional molecule binds to the presenter protein and a drug target to produce a tripartite complex, while in other embodiments the bifunctional molecule binds to either the presenter protein or the drug target, but not both, to produce a binary complex The subject methods and compositions find use in a variety of therapeutic applications.

We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells

Growing community of inventors

Menlo Park, CA, United States of America

Thomas J Wandless