If you are interested in collaborating or are working on ReACp53 on your own but want some advice or want to share some interesting results, reach out! Most importantly, if you are getting ReACp53 for your research be aware that there are vendors charging unreasonably high prices for profit - stay away from those! Just go to your favorite peptide synthesis company and order the peptide simply using its sequence, not its name. If you would like to receive our SOP to resuspend and handle the lyophilized peptide, send us an email.
Are you a patient or caregiver?
ReACp53 is not yet available as therapy to patients. The molecule was licensed to ADRx, Inc. which is currently testing its safety with the aim to proceed to clinical trials in the next future. If you want to know more about pre-clinical and clinical development of ReACp53, please contact ADRx, Inc.
p53 mutations are commonly found in cancers. Some p53 mutations destabilize the protein and facilitate its aggregation. ReACp53 is a cell-penetrating peptide designed to target and inhibit p53 aggregation and chaperone p53 to a soluble, functional state. ReACp53 causes cancer cells to die. We see that ReACp53 kills cancer cells carrying p53 mutations in:
3D tumor spheres
in vivo
The anti-tumor effect and absence of long-term toxicities in vivo are very encouraging. But, as with all novel molecules, there is much that we do not know yet about ReACp53. Is ReACp53 able to block full-length p53 aggregation in vitro? The short answer is NO. ReACp53 was designed to only arrest aggregation of a short stretch of residues in the p53 sequence. Nevertheless, p53 has many other segments equally aggregation prone that can push p53 clumping forward in vitro (even in the presence of ReACp53). In cells the situation is very different as the protein is not alone in solution. Many interacting partners (other proteins, chaperones, DNA) are present which means that only portions of the misfolded p53 are freely accessible and may be driving aggregation at any given time. The region immediately preceding the ReACp53-targeting sequence was shown to be solvent accessible in cells expressing mutant p53. Is ReACp53 targeting other proteins beside mutant p53? Yes!We have seen cell lines where silencing p53 expression completely abolishes ReACp53 response and others where it does not - whether it be because of incomplete silencing or other factors, tumor type, or mutation. We are currently investigating ReACp53 targeting of wild type p53 when the protein is over-expressed, accumulated and potentially misfolded in cancer. We are also studying p63 and p73. However, other, unrelated targets are also a possibility. What is the exact mechanism by which ReACp53 kills cancer cells? In our ovarian cancer 3D tumor spheres and in vivo, tumor cell death is compatible with p53 reactivation. Mutant p53 also gets efficiently degraded upon ReACp53 administration, hence removing a crucial oncogene. Which effect is more prominent might again depend on the specific p53 mutation, cancer type or both. Aggregates can sequester other seemingly unrelated proteins that are therefore inactivated. Removal of p53 and p53 aggregates may free these, rescuing their functions. In addition, other targets may also contribute to the anti-cancer effects seen (see above). Much remains to be investigated! Dosis sola venenum facit - The dose makes the poison. ReACp53, exactly like any other molecule, will eventually eliminate any cell in vitro if given at a high enough dose. This is expected. However, what surprised us was to observe that in 2D adherent cell models, ReACp53 activity is less specific than in 3D or in vivo toward mutant p53-expressing cells. Although 2D models are not faithfully recapitulating the tumor characteristics and environment, we are investigating this interesting phenomenon.