Isoxazoles - small molecule drugs

With the active involvement of its scientific founders and collaborators, LoneStar Heart is both using and developing leading edge technologies for the treatment of heart failure. Significant strides have been made though these collaborations to:

  • Define the cardiogenic pathway – from stem cell to heart muscle
  • Reprogram cells by switching genes and gene combinations “on” and “off”
  • Identify microenvironments where cardiac stem cells reside;
  • Screen and validate biologics and drugs that can control cardiac cell fate.

The scientific teams of Lone Star Heart’s co-founders, Dr. Eric Olson and Dr. Jay Schneider at the University of Texas Southwestern Medical Center (UTSW), have identified mechanisms that trigger native cardiac stem cells to regenerate the myocardium.  The UTSW team along with Dr. Doug E. Frantz in the Chemistry Department at University of Texas at San Antonio (UTSA) have now screened and validated in vitro a number of Isoxazole drug candidates that have the capacity to switch the stem cell behavior into a tissue-regenerative mode.

Strategy

Strategy for reducing cardiac fibrosis and inducing the myocardial repair pathway using small molecule drugs. Adapted with permission from Dr. Jay Schneider, UTSW, 2011.

Cardiac Applications

The objective consists of validating novel small-molecule based therapeutics that will pharmacologically trigger regenerative-repair from endogenous stem /progenitor cells of the human heart injured by myocardial infarction, degenerative or myopathic diseases.  Dr. Schneider and Dr. Frantz have shown that 3,5-disubstituted isoxazoles directed cardiac muscle gene expression in vivo in target tissues of adult transgenic reporter mice and also stimulated adult mouse myocardial cell cycle activity.  Isoxazoles directed muscle transcriptional programs in vivo in multipotent Notch-activated epicardium-derived cells (NECs), generating Notch-activated adult cardiomyocyte-like precursors.  Efficacy has been demonstrated for enhanced survival in an in vivo model of MI.  Current efforts are directed towards target validation for these Isoxazole molecules in the myocardium and screening Isoxazole analogues against this target.

Publications:

Russell JL, Goetsch SC, Aguilar HR, Frantz DE, Schneider JW. Targeting Native Adult Heart Progenitors with Cardiogenic Small Molecules. ACS Chem Biol. 2012;7(6):1067–76. doi:10.1021/cb200525q.

Russell JL, Goetsch SC, Gaiano NR, et al. A dynamic notch injury response activates epicardium and contributes to fibrosis repair. Circ Res. 2011;108(1):51–9. doi: 10.1161/circresaha.110.233262.

Russell, J. L., Goetsch, S. C., Aguilar, H. R.,  et al. (2012). Regulated Expression of pH Sensing G Protein-Coupled Receptor-68 Identified through Chemical Biology Defines a New Drug Target for Ischemic Heart Disease. ACS Chem Biol. doi:10.1021/cb300001m. 

Diabetes Application

A family of 3,5-disubstituted isoxazoles have also been shown to be neurogenic and will increase expression of NeuroD1 (also known as BETA 2).  This transcription factor functions in neuronal and pancreatic β-cell differentiation and is essential for insulin gene transcription.  Through collaboration with Dr. Melanie Cobb at UTSW, it has been shown that these Isoxazole molecules increased the expression and secretion of insulin in human cadaveric islets that made little insulin after prolonged ex vivo culture.  They also increased expression of regulators of islet differentiation and insulin gene transcription.  Therefore, these molecules have a potential for anti-diabetic activity.  We are currently identifying and validating the unique and distinct targets for these molecules in islets.  Also, in collaboration with Doug E. Frantz at UTSA, we are screening molecules targeted for the Diabetes application.

Publications

Dioum EM, Osborne JK, Goetsch S, et al. A small molecule differentiation inducer increases insulin production by pancreatic β cells. PNAS. 2011;108 (51):20713–8. doi:10.1073/pnas.1118526109