Structural biology behind a new cancer treatment
I saw this great write-up by Derek Lowe on a novel cancer therapeutic (and I say "cancer" generically on purpose, as this novel drug has a unique mechanism of action that may allow it to target a wide variety of different cancer types) and just had to dive into the structural biology of how it works.
Side note, Derek Lowe is a consistently great reporter of on science topics and I encourage everyone to subscribe to his blog "In the pipeline" which features his commentary on drug discovery and the pharma industry.
As far as I understand it, the drug AOH’s mechanism is that it prevents the healthy resolution of transcription-replication conflicts, which are solved in healthy cells by kicking off the RNA pol (pausing transcription) and allowing the replication fork to continue. When AOH is present, the RNA pol and the PCNA (ring clamp protein) associate strongly and that prevents the RNA pol from releasing. Physically, the RNA pol and ring clamp run into each other on the strand and 3 molecules of AOH bind at the interface, sticking the RNA pol to PCNA. The result is a fatal double strand break.
Since replication stress is already a chief source of cell stress in healthy cells, and cancer cells are doing much more transcription and replication than healthy cells, the AOH compound is selective against the cancer cells.
The authors report an average 30x difference between effective dose and toxic dose across a few dozen different cell lines (and a small mouse and dog study). Pretty interesting paper!
I suppose the next thing is we could design stronger and more selective binders to improve the headroom, or look for other binding sites on the RNA pol-PCNA complex to target. Pretty easy synthetic biology stuff if there’s an in vitro model that can be used to screen compounds in the lab.