Aprea AB

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Scientific Background

p53 is a prime target for novel first-line cancer therapies

  • p53 is a tumor suppressor protein that, in response to various forms of cellular stress, activates transcription of genes that induce cell cycle arrest (block of cell division) or apoptosis (programmed cell death)
  • Around 50% of human tumors have deficient p53, mainly due to mutations of the DNA-binding domain of the protein
  • p53 mutations result in loss of p53-dependent cell cycle arrest and apoptosis
  • In cancers where the gene itself is not mutated the p53 pathway is often partially inactivated
  • Aberrations in p53 or its regulators are associated with increased resistance to standard chemotherapy and hence poor prognosis
  • Therefore, reactivation of the p53 pathway is regarded as an attractive strategy for novel first-line cancer therapies  
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Schematic drawing - an artists impression of the p53 protein (core domain) bound to DNA. p53 specific DNA binding activates transcription of target genes that regulate cell cycle arrest and programmed cell death (apoptosis).

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Film clips about p53

(at YouTube, Aprea has no responsibility for the production or the content of the illustrations)xx

Molecular action of p53 in carcinogenesis

p53-DNA complex

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Unique finding - Small molecules can reactivate p53 function 

The founders of Aprea AB (Klas Wiman, Galina Selivanova, Vladimir Bykov, Staffan Strömblad, Wenjie Bao and Natalia Issaeva) have identified a molecule, APR-017 (also called PRIMA-1 in the litterature), that induces apoptosis through a p53-mediated mode of action.

Aprea AB has synthesized and screened a series of analogs belonging to the same chemical scaffold as APR-017. One of them, APR-246 (also called PRIMA-1MET), was selected as Aprea’s first Candidate Drug (CD). It has shown good results in various cancer models. In these studies pronounced anticancer effects, without any apparent side effects, have been observed. 

The back-up program of APR-246 focuses on orally active analogs, and several compounds with promising results have been identified. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
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