A First-in-Class MCL-1 degrader to promote apoptosis in therapy-resistant liquid and solid tumours

Description du projet

Dégradation ciblée des protéines pour les cancers résistants

De nombreux cancers dépendent de MCL-1, une protéine qui empêche la mort cellulaire programmée et entraîne une résistance à la thérapie. Bien que le blocage de MCL-1 soit une stratégie attrayante, les inhibiteurs conventionnels ont échoué à plusieurs reprises en raison d’une cardiotoxicité sévère. Le projet CT-03, financé par l’EIC, applique la dégradation ciblée des protéines pour relever ce défi. Au lieu d’inhiber MCL-1, leur petite molécule CT-03 la marque pour qu’elle soit éliminée par la machinerie naturelle d’élimination des déchets de la cellule. Les études précliniques montrent une forte dégradation de MCL-1 sans effets secondaires cardiaques chez les primates non humains. Le projet testera le CT-03 chez des patients atteints de leucémie myéloïde aiguë résistante à la chimiothérapie, dans le but de restaurer la sensibilité au traitement et de valider la sécurité. Des résultats positifs pourraient permettre l’octroi de licences et accélérer les traitements de nouvelle génération pour l’oncologie.

Objectif

Captor Therapeutics is a biopharmaceutical company pioneering the development of therapeutics for unmet medical needs using Targeted Protein Degradation. We focus on high-value drug targets that are “undruggable” by conventional approaches.
One such target is MCL-1, a protein preventing programmed cell-death. MCL-1 is implicated in resistance to cancer treatments. Due to its broad applications, developing a safe therapy that could hamper MCL-1's effect in cancer cells, would be a gamechanger for oncology. Unfortunately, MCL-1 inhibitors give rise to cardiotoxicity, which has led to the termination of several clinical trials.
Our unique TPD technology platform allows us to apply a radically different approach. We have developed a small molecule able to tag MCL-1 for degradation using the cellular waste protein disposal system. CT-03, positioned to become a First-in-Class MCL-1 degrader, has shown potent degradation, with no signs of cardiotoxicity in Cynomolgus monkeys, the closest translational bridge to humans.
Our first indication – AML (Acute Myeloid Leukaemia) – has a market size of €3.6bn. Currently, Venclexta is commonly used in AML patients unable to undergo ablative chemotherapy or hematopoietic stem cell transplantation. Unfortunately, nearly all AML patients eventually acquire resistance to Venclexta, which leaves them with no further treatment options. By degrading MCL-1, CT-03 will make resistant cells susceptible to conventional therapies again.
The project’s goal is to demonstrate safety and lack of cardiotoxicity in humans. Successful results from a Phase Ia/Ib trial on Venclexta-resistant AML patients will constitute a crucial inflection point for securing a lucrative out-licensing deal with a large pharmaceutical company. Our future partner will take CT-03 forward in AML and other poorly-treated cancers. Revenues from the out-licensing deal will be invested into advancing our clinical pipeline of protein degraders in oncology & neurodegeneration.