The present invention provides compounds of formula I: ##STR00001##
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds, and methods of using such compounds for treatment of joint damage or joint injury in a mammal, and for inducing differentiation of mesenchymal stem cells into chondrocytes.

The present invention provides compounds of formula I: ##STR00001##
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein the variables are as defined herein. The present invention further provides pharmaceutical compositions comprising such compounds, and methods of using such compounds for treatment of joint damage or joint injury in a mammal, and for inducing differentiation of mesenchymal stem cells into chondrocytes.

Described herein is a genetic modifier of cystic fibrosis (CF), which may serve as a predictor of the efficacy of a CFTR-directed therapy. SNPs rs7512462 or rs2869027 in non-coding regions of SLC26A9 are shown to correlate with CF lung disease severity in patients having CFTR mutations that leave protein at the cell surface, e.g. gating mutations such as G551D. It is also shown that patient response to Ivacaftor correlates with SLC26A9 genotype. Given the biology of SLC26A9, risk alleles of SLC26A9 should correlate with reduced SLC26A9. SLC26A9 activity (marked by e.g. genotype or expression level) is therefore a predictor of treatment efficacy for any CFTR-directed therapeutic, such as Ivacaftor or Lumacaftor. Associated methods of selecting and treating patients are described, along with related kits, uses, and drug discovery platforms.

Described herein is a genetic modifier of cystic fibrosis (CF), which may serve as a predictor of the efficacy of a CFTR-directed therapy. SNPs rs7512462 or rs2869027 in non-coding regions of SLC26A9 are shown to correlate with CF lung disease severity in patients having CFTR mutations that leave protein at the cell surface, e.g. gating mutations such as G551D. It is also shown that patient response to Ivacaftor correlates with SLC26A9 genotype. Given the biology of SLC26A9, risk alleles of SLC26A9 should correlate with reduced SLC26A9. SLC26A9 activity (marked by e.g. genotype or expression level) is therefore a predictor of treatment efficacy for any CFTR-directed therapeutic, such as Ivacaftor or Lumacaftor. Associated methods of selecting and treating patients are described, along with related kits, uses, and drug discovery platforms.

Methods for enhancing the activity of an ion transporter in a cell and/or treating a channelopathy in a subject based on the administration or use of an effective amount of a fenretinide compound (fenretinide, a fenretinide analog, or a pharmaceutically acceptable salt thereof) and/or zinc are described. The methods are useful for restoring or increasing the cell surface expression of an ion transporter such as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that is mutated or defective. The fenretinide compound and/or zinc may be used in combination with ion transporter modulators, e.g., CFTR modulators, to further enhance the cell surface expression and activity of the ion transporter.

Methods for enhancing the activity of an ion transporter in a cell and/or treating a channelopathy in a subject based on the administration or use of an effective amount of a fenretinide compound (fenretinide, a fenretinide analog, or a pharmaceutically acceptable salt thereof) and/or zinc are described. The methods are useful for restoring or increasing the cell surface expression of an ion transporter such as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) that is mutated or defective. The fenretinide compound and/or zinc may be used in combination with ion transporter modulators, e.g., CFTR modulators, to further enhance the cell surface expression and activity of the ion transporter.

The present disclosure provides, inter alia, bivalent small molecules and methods for treating or ameliorating the effects of a disease, such as long QT syndrome, or cystic fibrosis, in a subject, using the bivalent small molecules disclosed herein. Also provided are methods of identifying and preparing small molecule binders that target proteins of interest.

The application is directed to compounds of formulae (IA) and (IB): (IA) and (IB), and their salts and solvates, wherein R.sup.1a, R.sup.2a, .sup.A1, A.sup.2, A.sup.3, A.sup.4, R.sup.1b, R.sup.2b, B.sup.1, B.sup.2, B.sup.3, and G are as set forth in the specification, as well as to methods for their preparation, N pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Krabbe's disease, and α-synucleinopathies, such as Parkinson's disease.

##STR00001##

The application is directed to compounds of formulae (IA) and (IB): (IA) and (IB), and their salts and solvates, wherein R.sup.1a, R.sup.2a, .sup.A1, A.sup.2, A.sup.3, A.sup.4, R.sup.1b, R.sup.2b, B.sup.1, B.sup.2, B.sup.3, and G are as set forth in the specification, as well as to methods for their preparation, N pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Krabbe's disease, and α-synucleinopathies, such as Parkinson's disease.

##STR00001##

Methods of treating acute liver disease acute liver diseases are provided. Accordingly, there is provided a method of treating acute liver disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent capable of binding a component of a TLR-MYC signaling pathway selected from the group consisting of MYC, MYD88, TRIF and p38 and inhibiting expression and/or activity of the component.