Abstract: This disclosure relates to compounds that are cystic fibrosis transmembrane conductance regulator (CFTR) modulators and pharmaceutical compositions containing the same. In certain embodiments, this disclosure relates to methods of managing a CFTR related disease or condition or respiratory distress comprising administering an effective amount of a CFTR modulator disclosed herein to a subject in need thereof.

Abstract: In certain embodiments, this disclosure relates to methods of identifying cancer agents and treating cancer with identified agents. In certain embodiments, the caner agents are capable of inducing or stabilizing SMAD4 oligomerization.

Abstract: This disclosure relates to the discovery that a G12V mutant of KRAS (hereinafter KRAS G12V) binds to JAK1, i.e., the existence of a KRAS G12V and JAK1 binding interaction. In certain embodiments, this disclosure relates to methods of disrupting the KRAS G12V and JAK1 interaction reversing KRAS G12V induced immune escape by cancer cells utilizing agents that prevent the binding of JAK1 to KRAS G12V.

Abstract: This disclosure relates to asparagine endopeptidase inhibitors for managing cancer and compositions related thereto. In certain embodiments, the asparagine endopeptidase inhibitors are substituted 3,7-dihydropurine-2,6-dione derivatives useful for treating or preventing metastasis, tumor growth, and/or cancer. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising an asparagine endopeptidase inhibitor and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure relates to methods of treating a cancer comprising administering an effective amount of pharmaceutical composition a asparagine endopeptidase inhibitor disclosed herein to a subject in need thereof.

Abstract: This disclosure relates to asparagine endopeptidase inhibitors for managing cancer and compositions related thereto. In certain embodiments, the asparagine endopeptidase inhibitors are substituted 3,7-dihydropurine-2,6-dione derivatives useful for treating or preventing metastasis, tumor growth, and/or cancer. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising an asparagine endopeptidase inhibitor and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure relates to methods of treating a cancer comprising administering an effective amount of pharmaceutical composition a asparagine endopeptidase inhibitor disclosed herein to a subject in need thereof.

Abstract: This disclosure relates to asparagine endopeptidase inhibitors and compositions and uses related thereto. In certain embodiments, the asparagine endopeptidase inhibitors are useful for treating or preventing neurodegenerative diseases and cognitive disorders such as Alzheimer's Disease. In certain embodiments, the disclosure relates to pharmaceutical compositions comprising an asparagine endopeptidase inhibitor and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure relates to methods of treating or preventing a neurodegenerative disease comprising administering an effective amount of pharmaceutical composition a asparagine endopeptidase inhibitor disclosed herein to a subject in need thereof.

Abstract: Novel classes of molecular chaperone Heat shock protein 90 (Hsp90) inhibitors are disclosed. These compounds are useful in treating and preventing cancer and other Hsp90-related diseases and conditions, such as inflammation and neurodegenerative disorders. Methods of treating and preventing cancer and other Hsp90 related diseases and conditions are disclosed that include administering to the subject a therapeutically effective amount of an Hsp90 inhibitor. Methods of preparing the novel Hsp90 inhibitors are also provided.

Abstract: Methods are provided for enhancing the death of a neaplastic cell comprising the administration of a therapeutically effective concentration of a 14-3-3 antagonist and at least one antineoplastic therapeutic agent. The methods of the invention find use in improving the clinical outcome of a mammal having a neoplastic disorder and comprises administration to a mammal in need thereof at least one antineoplastic therapeutic agent in combination with a 14-3-3 antagonist. Further provided are pharmaceutical compositions having a therapeutically effective amount of a 14-3-3 antagonist and an antineoplastic therapeutic agent. Also provided are methods for identifying agents that selectively inhibit an interaction between a 14-3-3 polypeptide and a 14-3-3 ligand.

Abstract: Methods are provided for enhancing the death of a neaplastic cell comprising the administration of a therapeutically effective concentration of a 14-3-3 antagonist and at least one antineoplastic therapeutic agent. The methods of the invention find use in improving the clinical outcome of a mammal having a neoplastic disorder and comprises administration to a mammal in need thereof at least one antineoplastic therapeutic agent in combination with a 14-3-3 antagonist. Further provided are pharmaceutical compositions having a therapeutically effective amount of a 14-3-3 antagonist and an antineoplastic therapeutic agent. Also provided are methods for identifying agents that selectively inhibit an interaction between a 14-3-3 polypeptide and a 14-3-3 ligand.

Abstract: The present invention identifies a novel protein-protein interaction between Raf-1 and apoptosis signal-regulating kinase 1, thereby identifying a molecular basis for cross-talk between the Raf-1-mediated signaling and ASK-1-meditated apoptotic signaling. The invention provides methods for screening for agents that are capable of disrupting the disclosed protein-protein interaction or which are capable of modulating ASK1-mediated apoptosis. The invention further provides Raf-1 binding polypeptides, derived from the N-terminal regulatory domain of ASK1, that find utility as therapeutic agents, as reagents for establishing screening assays, as an immunogens to elicit peptide specific antibodies and as paradigmatic agents for the design or identification of small molecules that share a sufficiently similar structure so as to inhibit or promote the disclosed ASK1/Raf-1 interaction.

Abstract: The invention features a polypeptide consisting of amino acids 379-535 of diphtheria toxin, and portions thereof. This region, shown by X-ray crystallographic analysis to comprise the receptor binding domain of diphtheria toxin, is used as an immunogen and clinical therapeutic against diphtheria.

Abstract: The invention provides a cytotoxicity-based genetic selection (TOXSEL) method and related testing kit for the identification and positive selection of molecules or mutations that are capable of disrupting a specific protein--protein interaction. The invention enables positive selection of molecules disruptive of specific protein--protein interactions by virtue of the presence in the TOXSEL system of a toxin reporter gene. A disrupted protein--protein interaction precludes expression of the toxin reporter gene and, consequently, allows survival of the host cell. TOXSEL technology enables large-scale screening for drugs or small molecules capable of disrupting specific protein--protein interactions critical in processes such as cellular signalling, carcinogenesis, etc.