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

Descrizione del progetto

Degradazione mirata delle proteine per i tumori resistenti

Molti tumori dipendono da MCL-1, una proteina che impedisce la morte cellulare programmata e determina la resistenza alla terapia. Sebbene il blocco di MCL-1 sia una strategia interessante, gli inibitori convenzionali hanno ripetutamente fallito a causa della grave cardiotossicità. Il progetto CT-03, finanziato dal CEI, applica la degradazione mirata delle proteine per risolvere questa sfida. Invece di inibire la MCL-1, la loro piccola molecola CT-03 la contrassegna per essere eliminata dal naturale meccanismo di smaltimento dei rifiuti della cellula. Gli studi preclinici mostrano una forte degradazione di MCL-1 senza effetti collaterali cardiaci nei primati non umani. Il progetto sperimenterà CT-03 in pazienti con leucemia mieloide acuta resistente alla chemioterapia, con l’obiettivo di ripristinare la sensibilità al trattamento e convalidarne la sicurezza. I risultati positivi potrebbero consentire la concessione di licenze e accelerare i trattamenti di nuova generazione per l’oncologia.

Obiettivo

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.