‘Molecular glues’ that work by modulating protein–protein interactions are one of several emerging new types of drugs that are now beginning to see decades of work translate into success in clinical trials and drug approvals. US approval of Revolution Medicines’ Rasonque (daraxonrasib) to treat pancreatic cancer follows closely on the heels of accelerated approval for Bristol Myers Squibb’s Zenbexus (iberdromide) to treat multiple myeloma.
The two drugs work in different ways, but both fundamentally promote interactions between two target proteins to disrupt cancer’s progress. Iberdromide encourages the cell’s natural protein degrading machinery to identify and take out the transcription factor proteins that drive tumour cell multiplication. It builds on the success of thalidomide and related cancer drugs, but binds its targets more tightly together, making them more likely to activate the degradation process.
Daraxonrasib, on the other hand, interferes with Ras signalling – another crucial pathway in cell division and multiplication that is over-active in cancer cells. Like many of the processes that distinguish cancers from normal cells, this involves protein–protein interactions over relatively large surfaces. That means there isn’t a straightforward pocket or active site for a small molecule to bind to. For a long time, Ras proteins were therefore considered ‘undruggable’ with small molecules.
Daraxonrasib interferes with Ras signalling, which controls cancer cell division and has been difficult to target with other approaches to drug development
Daraxonrasib binds cyclophilin A – another large protein that is also present in all cells, but doesn’t normally bind to Ras – forming a complex that then grabs onto Ras and prevents it from participating in further signalling. The advantage of this approach is that it works on all three members of the Ras family, regardless of which of the many possible mutations is responsible for a particular patient’s cancer.
While daraxonrasib has so far been approved for pancreatic cancer, it’s likely that this or similar drugs will be successful in treating the many other types of cancer that also involve mutations in Ras proteins. Likewise, for iberdromide, its increased effectiveness may allow it or follow-up drugs to be effective beyond blood cancers like multiple myeloma, and help treat solid tumours in other tissues.
