STEM CELLS: MEDICINAL CHEMISTRY FOR CARDIAC REGENERATION
Dr. Dennis Schade
since 10/2012: Group leader, TU Dortmund University
2012: Postdoc, University of Kiel
2010-2011: Postdoc, Sanford-Burnham Medical Research Institute + Human BioMolecular Research Institute (San Diego, USA)
2005-2010: Postdoc, PhD studies, University of Kiel
1999-2004: Pharmacy studies (Kiel + West Haven, USA)
The field of regenerative medicine has boomed in recent years owing to milestone discoveries in stem cell (SC) biology and tissue engineering, which has been driving paradigm shifts in the pharmacotherapy of degenerative and ischemic diseases. Small molecule-mediated replenishment of lost and/or dysfunctional tissue in vivo, however, is still in its infancy due to a limited understanding of mechanisms that control endogenous processes of tissue homeostasis or regeneration. From the medicinal chemist's point of view, the development of small molecules that control SC fate is of tremendous interest for various applications as it opens up the druggable target space. Such applications do not only span small molecules as regenerative therapeutics for distinct diseases but also cover their use for SC-based technologies for safety pharmacology or disease modeling (i.e., disease-in-a-dish).
The Schade group is interested cardiovascular diseases with a particular focus on heart diseases and uses several SC-based techniques and approaches to cardiac regeneration. Hypothesis-driven approaches as well as screening campaigns are pursued to identify and develop small molecule modulators of key steps in cardiomyocyte (de-)differentiation and maturation from stem cells. This is an interdisciplinary strategy comprising methods from classic medicinal chemistry to (stem) cell and molecular biology.
- Synthetic organic chemistry: drug-like small molecule libraries, 'tool compounds'
- In vitro-pharmacokinetic profiling of drug candidates
- In silico-drug design: pharmacophore modeling
- Stem cells (SCs): murine embryonic SCs, human induced pluripotent SCs
- High-content imaging assays, cell-based assays + screening
Längle D, Halver J, Rathmer B, Willems E, Schade D. Small molecules targeting in vivo tissue regeneration. ACS Chem Bio 2014, 9(1), 57-71.
Plowright AT, Engkvist O, Gill A, Knerr L, Wang QD. Heart regeneration: opportunities and challenges for drug discovery with novel chemical and therapeutic methods or agents. Angew Chem Int Ed 2014, 53(16), 4056-75.
Schade D, Lanier M, Willems E, Okolotowicz K, Bushway P, Wahlquist C, Gilley C, Mercola M, Cashman JR. Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGFβ signaling. J Med Chem 2012, 55(22), 9946-57.
Willems E, Cabral-Teixeira J, Schade D, Cai W, Reeves P, Bushway PJ, Lanier M, Walsh C, Kirchhausen T, Izpisua Belmonte JC, Cashman J, Mercola M. Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells. Cell Stem Cell 2012, 11(2), 242-52.