Searching for new ways to block the growth of cancer cells has always been a daunting task for researchers. Tumor cells rely on numerous proteins to function, making it challenging to find precise drug targets. However, a team at Scripps Research and the Broad Institute of Harvard and MIT has developed a groundbreaking method to identify new drug targets with the potential to impact multiple types of cancers.
The researchers used a precise gene editing approach to modify over 13,000 potential drug targets. By determining which edits affected cell growth and integrating this information with chemical proteomic data, they identified hundreds of possible drug targets, many of which have not been explored in previous research.
Over the past decade, research chemists and pharmaceutical companies have become interested in drugs that permanently bind to cysteines, one of the twenty amino acids that constitute all human proteins. Cysteine’s unique reactive chemistry makes it an ideal drug target. However, with hundreds of thousands of cysteines scattered among human proteins, determining which cysteines to target is exceptionally challenging. Even among the few thousand proteins considered critical for cancer cell growth, there are still over 13,000 cysteines to consider.
To narrow down the list, the researchers needed a way to identify cysteines with significant functional impacts on cancer-relevant proteins. Inspired by a genetic variation approach used by Stuart Schreiber at the Broad Institute, postdoctoral research associate Haoxin Li proposed combining precise genome engineering techniques with cutting-edge chemical proteomic tools to discover potential cancer therapeutics.
Base Editing for Targeted Changes
During Li’s collaboration with Scripps Research, he worked alongside David Liu, a core member of the Broad Institute, who developed base editing – a method for precisely altering DNA letters. Li utilized base editing to introduce targeted amino acid changes in cancer cells. By generating various cysteine-targeted mutations, he aimed to determine which cysteines were most crucial for cancer cells.
In their extensive study, Li, Cravatt, and their colleagues edited more than 13,800 locations on over 1,750 genes linked to cancer cell survival. Each edit targeted a cysteine on the corresponding protein, and the researchers assessed the growth of the edited cancer cells. They also integrated their findings with new data on the “druggability” of these cysteines.
Ultimately, the team discovered that roughly 160 of the druggable cysteines, when edited, influenced cancer cell growth. This suggests that drugs targeting these specific cysteines could potentially be effective in treating cancer. One of the edits with significant impacts was made to the cancer-dependency protein TOE1, which had not been studied as a cancer drug target before. The researchers showed that small molecules could be used to target TOE1, inhibiting its normal activity and potentially impacting cancer cell growth.
While further research is necessary to determine if a drug targeting TOE1 could be beneficial for human patients, the initial results demonstrate the effectiveness of editing cysteines in predicting potential drug targets. The researchers plan to explore other novel targets revealed by their experiments and develop the next generation of chemical genetic approaches to study druggable cysteines in diseases beyond cancer.
The discovery of new drug targets for cancer treatment is a challenging task. However, the use of precise gene editing and integration with chemical proteomic information has provided unprecedented insights into potential drug targets. This innovative approach brings us one step closer to developing effective treatments that can impact multiple types of cancers.
Authors of the study include Benjamin Cravatt, Haoxin Li, Jarrett Remsberg, Sang Joon Won, Kristen DeMeester, Evert Njomen, Daisuke Ogasawara, and Bruno Melillo of Scripps Research. Additionally, Kevin Zhao, Tony Huang, Stuart Schreiber, and David Liu of the Broad Institute of Harvard and MIT, Bingwen Lu and Gabriel Simon of Vividion Therapeutics, and Tiantai Ma and Jens Lykke-Andersen of UC San Diego contributed to the research.