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

Descripción del proyecto

Degradación selectiva de proteínas en tumores resistentes

Muchos tipos de cáncer dependen de MCL-1: una proteína que impide la muerte celular programada y favorece la resistencia a la terapia. La inhibición de MCL-1 c es una estrategia prometedora, pero los inhibidores convencionales no han logrado resultados efectivos debido a la aparición de cardiotoxicidad grave. En el proyecto CT-03, financiado por el Consejo Europeo de Innovación, se empleará la degradación selectiva de proteínas para superar esta limitación. En lugar de inhibir MCL-1, la pequeña molécula CT-03 lo etiqueta para su eliminación mediante el sistema natural de eliminación de residuos de la célula. Los estudios preclínicos muestran que CT-03 provoca una degradación eficaz de MCL-1 sin efectos secundarios cardíacos en primates no humanos. El equipo del proyecto evaluará la molécula CT-03 en pacientes con leucemia mieloide aguda resistente a la quimioterapia, con el objetivo de restaurar la sensibilidad al tratamiento y confirmar su seguridad. En caso de obtener resultados positivos, CT-03 podría ser licenciado a otras empresas, acelerando así la creación de tratamientos oncológicos de nueva generación.

Objetivo

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.