@article {13516, title = {SLMP53-1 interacts with wild-type and mutant p53 DNA-binding domain and reactivates multiple hotspot mutations}, volume = {1864}, year = {2020}, note = {n/a}, month = {2020}, pages = {129440}, abstract = {

BackgroundHalf of human cancers harbour TP53 mutations that render p53 inactive as a tumor suppressor. As such, reactivation of mutant (mut)p53 through restoration of wild-type (wt)-like function represents one of the most promising therapeutic strategies in cancer treatment. Recently, we have reported the (S)-tryptophanol-derived oxazoloisoindolinone SLMP53-1 as a new reactivator of wt and mutp53 R280K with in vitro and in vivo p53-dependent antitumor activity. The present work aimed a mechanistic elucidation of mutp53 reactivation by SLMP53-1.
Methods and results
By cellular thermal shift assay (CETSA), it is shown that SLMP53-1 induces wt and mutp53 R280K thermal stabilization, which is indicative of intermolecular interactions with these proteins. Accordingly, in silico studies of wt and mutp53 R280K DNA-binding domain with SLMP53-1 unveiled that the compound binds at the interface of the p53 homodimer with the DNA minor groove. Additionally, using yeast and p53-null tumor cells ectopically expressing distinct highly prevalent mutp53, the ability of SLMP53-1 to reactivate multiple mutp53 is evidenced.
Conclusions
SLMP53-1 is a p53-activating agent with the ability to directly target wt and a set of hotspot mutp53.
General Significance
This work reinforces the encouraging application of SLMP53-1 in the personalized treatment of cancer patients harboring distinct p53 status.

}, keywords = {Cancer, Chemotherapy, Mutant, p53, Reactivator}, isbn = {0304-4165}, url = {http://www.sciencedirect.com/science/article/pii/S0304416519302260}, author = {Gomes, Ana Sara and Ramos, Helena and Gomes, Sara and Loureiro, Joana B. and Soares, Joana and Barcherini, Valentina and Monti, Paola and Fronza, Gilberto and Oliveira, Carla and Domingues, Luc{\'\i}lia and Bastos, Margarida and Dourado, Daniel F.A.R. and Carvalho, Ana Lu{\'\i}sa and Rom{\~a}o, Maria Jo{\~a}o and Pinheiro, Benedita and Marcelo, Filipa and Carvalho, Alexandra and Santos, Maria M.M. and Saraiva, Luc{\'\i}lia} }