INTRODUCTION: The majority of human sarcomas, particularly soft tissue sarcomas, 
are relatively resistant to traditional cytotoxic therapies. The 
proof-of-concept study by Ray-Coquard et al., using the Nutlin human double 
minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in 
the molecular targeting of human sarcomas.
AREAS COVERED: In this review, the authors discuss the challenges and 
prospective remedies for minimizing the significant haematological toxicities of 
the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart 
the future direction of the development of p53-reactivating (p53-RA) drugs in 
12q13-15 amplicon sarcomas and as potential chemopreventative therapies against 
sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the 
therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the 
potential pitfalls, which may lie in ahead for the future clinical development 
of p53-RA agents, as well as discussing potential non-invasive methods to 
identify the development of drug resistance.
EXPERT OPINION: Medicinal chemistry strategies, based on structure-based drug 
design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding 
antagonists into less haematologically toxic drugs. In silico modelling is also 
required to predict toxicities of other p53-RA drugs at a much earlier stage in 
drug development. Whether p53-RA drugs will be therapeutically effective as a 
monotherapy remains to be determined.