Prosetta has applied the logic of catalyzed assembly that arose so successfully from its anti-viral work to other human diseases, including cancer. This work has revealed that the normal-to-aberrant assembly machine transition that Prosetta has identified for viruses applies also to non-viral diseases. It concludes that the same relatively small set of metabolic “weak links” that viruses have found and exploited are at risk of modification in response to the mutations, environmental toxins and other influences that lead to cancer. Hence, cancer cells are also predicted to contain aberrant assembly machines that are essential for the cancerous state and can be specifically targeted by small molecules.
Prosetta tested this logic using its Hitfinder Collection, roughly 300 molecules identified in Prosetta’s initial cell free screens for inhibition of capsid assembly in at least one of the 23 families of viruses that cause human disease (Prosetta tested 20 of the 23 families). Use of the Hit Finder Collection in a cell-based assay for inhibition of proliferation of a cancerous cell line has led to stunning results that Prosetta continues to explore and develop. The hits that resulted were non-toxic to healthy cells, failing to stimulate their apoptosis, but very effectively arrested the proliferation of the cancer cells and caused their death by endogenous apoptosis or some other unidentified but specific mechanism. This result applies not only to the original cell line used in the screen, but apparently to cancerous cell lines in general, regardless of origin. Thus, when an external collaborator independently tested a set of Prosetta anti-cancer chemotypes, Prosetta’s initial results were both validated and expanded by the demonstration of activity in 16 of 16 unrelated cell lines from cancers of different types. Two of these chemotypes, hitting two different aberrant assembly machines present in all of these cancer cell lines, have been tested successfully and without general toxicity in three of three mouse xenograft trials of human cancers for lung and colon cancer.
Prosetta’s evidence suggests that these compounds act by interfering with assembly machines that are unique to the cancerous state. This may represent a much more physiological approach than conventional anticancer chemotherapy. Prosetta’s approach is also completely unrelated to current immunological approaches, for which a major liability is the huge cost of more and more narrowly targeted therapeutics. In contrast, targeting assembly machines that are a common feature of cancer offers the promise of lower cost and lower toxicity cancer therapeutics compared to the current standard of care.