What happened to BBR3464 and where to from here for multinuclear platinum-based anticancer drugs?

Abstract

The development of the trinuclear platinum(II) complex BBR3464 (also known as triplatin) in the late 1990s was meant to be a revolution in the field of platinum chemotherapy. What made it remarkable was that it defied many of the known structure–activity rules for platinums; it is cationic, has a single labile trans leaving group on each terminal platinum, and it binds DNA in ways different to mononuclear platinum drugs, like cisplatin and oxaliplatin. The flexible, long-range adducts the drug forms with DNA means that it showed activity in cancers not typically sensitive to platinums, and more importantly, BBR3464 demonstrated an ability to overcome acquired resistance to platinum drugs. But while preclinical and phase I testing showed promise, its more severe side effects which greatly limited the deliverable dose when compared with standard platinums, combined with its lack of biostability, led to a lack of activity in phase II trials and its development was halted. But, from its ashes have risen 4^th generation complexes which target the phosphate backbone of DNA. These, and the original BBR3464 drug, could potentially be further developed and gain regulatory approval through formulation with macrocycle-based drug delivery vehicles.