“Science is the thing that keeps me up all night,” said Georg Winter, reflecting on what inspired him to pursue a post-doc at Dana Farber Cancer Institute/ Harvard Medical School, and led to his present position at CeMM – the Research Center for Molecular Medicine of the Austrian Academy of Science. Winter clearly loves his chosen field: “It has always been great fun,” he says,” to spend long hours in the lab.”
Winter’s lab at CeMM investigates ways to combat cancer cells by interfering with their genetic regulation. Cancer cells produce molecules for the pathways leading to abnormal cell growth, and some of those factors regulate transcription – the conversion of genetic information from DNA into RNA. One way to inhibit or block the progression of cancer is to target the production of cancer-related transcription factors.
Past therapeutic approaches have targeted these factors using specific small molecules designed to bind to them at a specific location, blocking access to that site. This is called competitive inhibition, because the small molecules block/inhibit that site’s usual function. Small molecules can disable their protein targets, but the report by Winter et al. in Science, notes that the effects are limited due to the brief association-and-dissociation between the small molecule and its target, and because many target proteins have multiple active sites.
Winter’s lab, using techniques developed during his post-doc at Dana Farber, took a new approach by linking those small molecules to phthalimide derivatives. The small molecules still bind to the targeted transcription factor, but the linked phthalimide offers advantages: causing immediate degradation of the targeted protein, as well as more-rapid cell death (evidenced by cell chemistry and viability) than in competitive inhibition. Not only did they achieve target protein degradation in cultured human leukemia cells, but the approach also slowed leukemia progression in a mouse engrafted with human leukemia. This made phthalimide-linked small molecules the first such system to induce target-protein degradation in vivo.
“Using small molecules to understand and disrupt gene regulation in cancer is an exciting field in truly amazing times to do science,” observed Winter. He is convinced that their work on targeted protein degradation will lead to novel drug candidates and be tested in patients within two years. “If this technology, or drugs designed based on these simple principles [i.e., linking target-specific small molecules with phthalimides to rapidly degrade cancer-related transcription factors or another harmful protein target], will help patients in the not-too-distant future,” he said, “I would be amazingly happy and satisfied.”
Georg Winter studied Biotechnology and performed his undergraduate studies with Thomas Jenuwein at the IMP in Vienna. He undertook his graduate studies with Giulio Superti-Furga at CeMM and continued his training as a postdoctoral fellow with James Bradner at the Dana Farber Cancer Institute/ Harvard Medical School. He joined CeMM in 2016.
The preceding article is part of a series featuring the scientific work of 20 young Austrian researchers, all who are active members of the OSTA's Research and Innovation Network Austria. The initial presentation of their work took place at the ASCINA poster session under the auspices of the "Austrian Research and Innovation Talk" in Toronto on October 21, 2016. Three of these scientists were subsequently awarded the ASCINA award the same evening, honoring their outstanding scientific work.