Drugging the undruggable: targeting RNA-binding proteins as a therapeutic avenue against ovarian cancer — ASN Events
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Drugging the undruggable: targeting RNA-binding proteins as a therapeutic avenue against ovarian cancer (#105)

Jean Borges Bertoldo 1 , SImon Müller 2 , Nadine Bley 2 , Markus Glass 2 , Jacob Haase 2 , Barbara Bernardim 3 , Emma Yates 3 , Francisco Corzana 4 , Tiago Rodrigues 5 , Christian Ihling 2 , Ehab Ghazy 2 , Andrea Sinz 2 , Wolfgang Sippl 2 , Gonçalo Bernardes 3 , Stefan Hüttelmaier 2
  1. Children's Cancer Institute Australia, UNSW, Randiwck, NSW, Australia
  2. University of Halle-Wittenberg, Halle, Germany
  3. University of Cambridge, Cambridge, United Kingdom
  4. University of La Rioja, La Rioja, Spain
  5. University of Lisbon, Lisbon, Portugal

Background: RNA-binding proteins (RBPs) are critical players in oncogenesis and cancer progression, and hence promising drug targets. However, they are considered “undruggable” due to complex nature of RNA-protein interactions, lack of binding pockets and intrinsically disordered regions.

Aims: Accordingly, we have developed a conceptually new approach to drug these proteins by a rational modification of specific residues using innovative chemical probes.

Methods and Results: We initially adapted a site-selective protein modification approach (chemical editing) to identify functionally relevant and druggable cysteines in the oncofetal and pro-oncogenic IGF2 mRNA binding protein 1(IMP1). Subsequently, we tested the druggability of the identified residues by employing computational chemistry, cysteine-directed probes and cell-based chemical biology tools. Our efforts have uncovered residues C253 and C336, which were directly linked to IMP1 pro-oncogenic activity, and the discovery of J5 as a dual targeting covalent inhibitor. J5 impaired tumour growth and metastasis of ovarian cancer xenografts by the cysteine-specific modification of C253 and C336, which led to selective deregulation of IMP1-enhanced oncogene expression.

Conclusions: These results demonstrate the potential of our approach to discover and enable the rational modification of functionally relevant cysteines in RBPs as an innovative cancer therapy

 

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