The Molecular Army (aka habemus DDR1 inhibitor)

It takes a small army to make a molecule. The one on top is ours and the team below is the small DDR1 troop.

We started to work on this master regulator of the extracellular matrix back in 2010. Many problems to fix, a lot of unknown biology and technical difficulties that seemed to pile up endlessly: difficulty to produce the protein, difficulty to create an inducible cell line, an high throughput screen that really didn't deliver much and a very negative scaffold-hopping effort, etc, etc...). But we kept working.

The success came in the shape of a parallel DNA-encoded technology (DELT) screen run by the magician of this technology within Roche (Alex Satz, 4th from left in the photo). A very first effort performing DELT on so very close receptors (DDR1 and DDR2 share 99.5% homology, pretty tough). The initial hit was then transformed by the chief magician chemist (Hans Richter, 1st from right). Hans was guided in his chemistry by the precise modeling of Bernd Kuhn (second from right). Franziska Weibel (second from left), column of my lab during many years @ Roche, flew to Miami to transfer the in vitro assay to a skilled team of academic scientists. The molecule in the meantime was stabilized, transformed, tested, etc, etc by all the other team members (only some of them in the photo). Finally, Alessia Fornoni and his team tested the compound in the mouse model of Alport syndrome, many years after we started to discuss about this target in a bar here in Basel, Switzerland. If this is not magic, tell me what is.

Paper is now available on ACS Chem Biol paper: https://pubs.acs.org/doi/pdf/10.1021/acschembio.8b00866

Bye, bye DDR1