Leland Stanford Junior University

Harvard College

Other

Purdue Research Foundation

Sara Lee Corporation

Howard Hughes Medical Institute

Erasmus University Medical Center Rotterdam

Gerald R Crabtree

Thomas J Wandless

Stuart L Schreiber

Peter Belshaw

David M Spencer

Steffan Nicholas Ho

Jeffrey P Northrop

Roger Briesewitz

Isabella A Graef

William Michael Flanagan

Kurt William Vogel

Emily Carla Dykhuizen

Cigall Kadoch

Gregory Thomas Ray

Jason E Gestwicki

Dirk B Mendel

David Spencer

Richard J Bram

Tokameh Mahmoudi

Stephen D Liberles

Emma J Chory

Diana Clare Hargreaves

Feng Chen

Kryn Stankunas

Steffan N Ho

This disclosure provides methods of using BAF complex modulating compounds as inhibitors of BAF-mediated transcription in target cells. The BAF complex modulating compounds include 12-membered macrolactam compounds that can target a BAF-specific subunit (e.g., ARID1A) to prevent nucleosomal positioning, relieving transcriptional repression of HIV-1. The subject methods can provide for reversal of latency of HIV-1 in cells in vitro or in vivo. Use of the macrolactam BAF complex modulating compounds represent a method of HIV latency reversal with a unique mechanism of action, which can be optionally combined with other Latency Reversal Agents to improve reservoir targeting. The subject methods can be utilized in conjunction with any convenient methods of treating HIV or HIV latency, including methods related to immune system activation, antiretroviral therapies and/or anti-HIV agents.

Methods for reversing HIV latency using BAF complex modulating compounds

The invention provided here creates a new paradigm for the treatment of a variety of conditions where modulation of a BAF complex is desired. The disclosure that follows outlines a strategy for modulating a BAF complex in a cell, and provides effective compounds, pharmaceutical compositions, development strategies, and treatment protocols, and describes many of the ensuing benefits. A new family of BAF complex modulating compounds has been developed based on a new chemical scaffold including a 12-membered macrolactam core structures. Contacting target cells in vitro or in vivo with the compounds and compositions of this invention can selectively inhibit the activity of BAF complexes in such cells. Some of the BAF complex modulating compounds in this family are particularly effective agents for treating cancer in conjunction with a ATR inhibitor.

BAF complex modulating compounds and methods of using the same

Methods for identifying and treating cancer patients likely to respond to topoisomerase inhibitors or likely to fail to respond to topoisomerase inhibitors are provided. The methods take advantage of the newly discovered role of BAF complexes in decatenation of DNA by topoisomerase IIa. Cancer cells are frequently at least partly defective in BAF complex activity. Such cells are targeted for therapy using certain topoisomerase IIa inhibitors according to the disclosed methods of treatment. Therapy of such cells using other topoisomerase inhibitors should be avoided.

Methods for identifying and treating cancer patients

Methods and compositions are provided for treating human synovial sarcoma (SS). Also provided are screens to identify therapeutics for the treatment of synovial sarcoma. These methods, compositions, and screens are based on the discovery that promoting the assembly of wild type BAF (also called mSWI/SNF) complexes in SS cells by increasing levels of wild type SS18 and/or decreasing levels of SS18-SSX fusion protein leads to the cessation of proliferation of malignant cells in synovial sarcoma.

Methods, compositions and screens for therapeutics for the treatment of synovial sarcoma

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

Methods and compositions are provided for reducing aggregation of neurodegenerative proteins associated with neurotoxicity or other proteins. The compounds comprise a first domain or targeting element for binding to the target proteins linked to a second domain or recruiting element that binds to an aggregation inhibiting protein, e.g. a prolyl isomerase. By associating the aggregating forming proteins or neuronal cells under conditions where aggregating proteins are produced with the compound and the aggregation inhibiting protein, aggregation is reduced. The subject agents can be used in assays, investigating the etiology of the neuronal diseases and for prophylaxis and therapy.

Neurodegenerative protein aggregation inhibition methods and compounds

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

Methods and compositions for modulating angiogenesis in a host are provided. In the subject methods, an effective amount of Ca/calcineurin/NF-ATc signaling pathway modulatory agent is administered to the host. In many embodiments, the Ca/calcineurin/NF-ATc signaling pathway modulatory agent is an NF-ATc antagonist, e.g., in those embodiments of inhibiting angiogenesis. The subject methods find use in a variety of different applications, including the inhibition of tumor growth and the treatment of disease conditions characterized by tumor presence. Also provided are methods of screening for agents that inhibit angiogenesis by modulating the Ca/calcineurin/NF-ATc signaling pathway.

Methods and compositions for modulating angiogenesis

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

Materials and methods are disclosed for regulation of biological events such as target gene transcription and growth, proliferation or differentiation of engineered cells.

Dimerizing agents, their production and use

This invention is directed to a modified cyclosporin A and to a modified, genetically engineered version of its receptor, cyclophilin. This invention is further directed to a method for treating host versus graft disease following blood marrow transplantation by transfecting stem cells so that after introduction into a patient the stem cells will express the modified cyclophilin, and, as necessary, administer the modified cyclosporin A to the patient.

Growing community of inventors

Woodside, CA, United States of America

Gerald R Crabtree