1-Synthesize a great number of diverse classes of retinoids and rexinoids; combinatorial synthesis of large families of lead derivatives.
2-Determine RAR/RXR isotype selectivity and cross-reactivity with other nuclear receptors in living cells; classify as agonists, neutral and partial antagonists, and inverse agonists.
3-Define the effect of the different classes of retinoids and rexinoids on composition and dynamics of coregulator complexes.
4-Identify "dissociated" ligands that selectively repress AP1 action; analyse the molecular basis.
5-Identify retinoids and rexinoids that affect blood and solid tumor cell proliferation, differentiation, survival and apoptosis.
6-Study the synergism with methylation, HDAC inhibitors and chemotherapeutic drugs to assess the possibility of combination therapy.
7-Study implication of tumor-specific TRAIL death signaling in apoptogenic retinoid and rexinoid action.
8-Explore the mechanisms of antiviral activity.
9- Establish skin pharmacology.
Complex (transcription Regulation/DNA) Retinoid X Receptor-Thyroid Hormone Receptor DNA-Binding 2 Domain Heterodimer Bound to Thyroid Response Element DNAPDB code: 2NLL Swissprot ref: P19793/P10828
One group specialised on retinoid chemistry will, assisted by molecular modeling, generate a large number of diverse classes of retinoids and rexinoids. As soon as the first compounds become available they will be channelled into a high throguput cell-based screening procedure to determine RAR and RXR isotype selectivity, cross-reaction with other (orphan) nuclear receptors and crosstalk capacity. In vitro receptor binding of positively scoring compounds will be assessed. Families of derivatives of identified leads will be generated by combinatorial, solid-(or solution)phase high-througput synthesis.
In parallel 3 research axes will be initiated, (1) determination of the coregulator interaction pattern which will provide mechanistic information and guide synthesis; (2)study of the effects of lead compounds on differentiation, cell cycle progression, survival and apoptosis, both a the cell biological (FACS), biochemical (caspase activation) and molecular level (activation of key regulatory factors). Particular attention will be given to tumor-selective action of TRAIL signaling. The cellular systems investigated will include blood (myeloid leukaemia and B cell lymphoma) and solid (keratinocytes; breast tumors) cancers; (3) the antiviral activity of leads, especially those repressing AP1, will be determined in 2 systems: Herpes and Epstein-Barr virus-infected cells. Focus will be on key genes known to trigger viral replication and transformation of host cells.
The interplay between chemists, modellers, molecular biologists, biochemists and virologists will be iterative and interdigitated to speed up the synthesis, detection and characterisation of promising novel classes of anticancer ret(x)inoids.
For the promising leads the skin pharmacological potential will be established and their activity in the prevention of chemically induced skin and breast cancer will be assessed in established animal models. Finally, the mechanisms of action of leads wil be scrutinized.
1-Generation of novel ret(x)inoids with diverse isotype selectivities and functionalities.
2-Identification of ret(x)inoids which alone, or with other drugs, kill/inhibit growth of cancer cell with little/no effect on the survival of normal cells.
3-Identification of ret(x)inoids with antiviral action.
4-Definition of the molecular mechanism of ret(x)inoid anticancer and antiviral action.
5-Definition of the ligand effects on coregulator interaction patterns.
6-Initial pharmacology of leads.
Last updated: 11.01.2005