Our aim is to provide important contributions to the discovery and development of new drugs for a more efficient treatment of severe human diseases. Our group is developing novel selective compounds against major human diseases ( see overview), which are currently not or insufficiently treatable with available drugs. Each research project in guided by at least one of the following principles:
Our expertise in drug development reaches from discovery of first “hits” to the in-vivo testing in the preclinical stage. Not only we are using state-of-the art methodology of medicinal and computational chemistry, but also we are developing appropriate and reliable biochemical and cellular assays in house to measure compound activity (e.g. P2-Subproject) . In addition, a novel MS/MS-based screening method is under development. Whenever appropriate, we apply a rational approach (e.g. computer modelling in combination with virtual screening), followed by chemical synthesis of structurally interesting and promising new compounds and subsequent activity testing in vitro. Several cellular and non-cellular screening systems which have been developed by our group can be applied. We are using partially isolated protein extracts, cell free enzyme and membrane preparations as well as various mammalian cell lines, yeast and bacterial strains which, in many cases, have been transformed through recombinant expression of the respective human enzymes of interest. All throughout the compound optimisation process, compounds are screened in parallel against highly homologous non-target enzymes to monitor selectivity.Depending on the requirement of the project, compounds are optimised in iterative cycles comprising parallel synthesis, activity screening, molecular docking and modelling, and, not at the least, experience and instinct of our medicinal chemists. Compounds which have been developed further and have proven to be highly active in vitro are subjected to in vivo tests. Further preclinical and clinical development is performed through cooperation with partners from industry. As an example, our original design of non-steroidal inhibitors of aromatase has successfully contributed to the development of selective compounds which are now in clinical use as first-line therapeutics against estrogen-dependent breast cancer in the U.S. after surgical treatment. |
| Project |
Indication(s) |
Scientific particularity |
Compound mechanism of action |
Discovery/ development strategy |
| P1: Development of CYP 17 (P450 17) inhibitors for an improved anti-androgen treatment of prostate cancer more informations |
Prostate Cancer |
Proven treatment strategy of blocking androgen action is exploited in a more efficient, novel way: inhibition of androgen production rather than receptor antagonists |
Heme-complexing, steroid mimicking |
No X-ray structure available; molecular modelling approach, combined with screening of focused in-house compound library |
| P2: |
Heart failure, myocardial fibrosis, and hyperaldosteronism |
A new target was chosen by us to develop novel compounds with reduced side effects while relying on a proven therapeutic principle |
Heme-complexing, steroid mimicking |
No X-ray structure available; molecular modelling approach, combined with screening of focused in-house compound library |
| P3: Novel Concept for Dual Inhibition of 5 α -Reductase more informations |
Benign Prostatic Hyperplasia (BPH) |
Inhibition of both 5 α -Reductase isoforms by using a pro-drug concept (hybrid inhibitor); non-steroidal inhibitor structure will avoid side-effects attributable to the presently marketed steroid-like drugs. |
Non-steroidal precursor drug (inhibitor of 5 α -Reductase type 1) is converted to the corresponding 5 α -Reductase type 2-inhibitor by prostatic esterases.
|
No X-ray structure available; molecular modelling approach, combined with screening of focused in-house compound library; pharmacokinetic evaluation |
| P4: Selective inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): A promising approach for the treatment of hormone-dependent female disorders more informations |
Estrogen-dependent diseases such as breast cancer and endometriosis |
Novel intracrinological approach aiming at high tissue specificity and low side-effects |
Steroid mimicking competitive inhibitors devoid of estrogenicity |
Rational design based on X-ray structure; differential docking of candidate compounds to estrogen receptor structure |
| P5: Ligands of the human CD81 protein: Pharmacological tools that offer novel treatment options for hepatitis C virus infection more informations |
Hepatitis C virus infections |
Novel target for Drug development; big medical need for specific antiviral treatment |
Compounds compete with binding of viral E2 glycoprotein and prevent viral entry |
Molecular modelling based on X-ray structure, virtual screening and rational design |
| P6: Development of high-throughput screening (HTS) methods for compound libraries based on MS/MS detection more informations |
- not applicable - |
Flexible, HTS compatible method for identifying ligands out of a complex mixture of compounds; main advantages: speed, label free |
Compounds are identified based on affinity interaction with the target |
- not applicable - |
| P7: Development of novel non-ATP competitive drugs that inhibit protein kinases of the AGC family more informations |
Several forms of cancer, diabetes type-2 |
First small molecules rationally designed as allosteric effectors of the activity of a whole family of protein kinases |
Binding to allosteric docking site modulates activity by conformational changes; non-ATP competitive properties anticipate better selectivity |
Combined approach of peptide-guided strategy, library screening and virtual screening |