The role of STRIs in cancer

What role does the eIF4F complex play in cancer, and how do your STRIs target it?

 eIF4F is a critical biomolecular complex that plays a central role in cancer development and progression. It is responsible for initiating the translation of specific messenger RNAs (mRNAs) into proteins within cells. These proteins are often oncogenes or other factors that have a profound effect on cells, including driving cancer cell growth, proliferation, and survival. Because these proteins have such a profound effect on cells, there is typically a second hurdle of regulation that needs to be overcome to make the proteins. That second hurdle is translation initiation, activated by eIF4F. In cancer, the eIF4F complex becomes dysregulated, leading to the excessive production of these proteins, which contribute to tumour formation and resistance to treatment.

eFFECTOR Therapeutics has developed a novel class of cancer drugs known as Selective Translation Regulator Inhibitors (STRIs), which directly target the eIF4F complex. STRIs, such as our clinical candidates tomivosertib and zotatifin, are designed to selectively inhibit the function of this complex, preventing it from initiating the translation of cancer-promoting proteins. Specifically, tomivosertib targets mitogen-activated protein kinase interacting kinase (MNK) 1 and 2, while zotatifin inhibits eukaryotic initiation factor 4A (eIF4A). By disrupting the eIF4F complex, STRIs effectively cut off the overproduction of these cancer-driving proteins, sabotaging the critical pathways that support tumour growth, immune evasion, and resistance to treatment.

This approach is highly targeted, as STRIs selectively inhibit the translation of a specific network of disease-causing proteins without affecting the broader cellular machinery. By directly interfering with the eIF4F complex, eFFECTOR’s STRIs provide a promising avenue for disrupting the core mechanisms of cancer, offering the potential to improve patient outcomes and overcome the limitations of traditional cancer therapies.

How do STRIs differ from traditional cancer therapies, and what advantages do they bring?

STRIs represent a fundamentally different approach to cancer therapy compared to traditional treatments like chemotherapy, radiation therapy, and targeted therapies. The key differences lie in their mechanism of action and potential advantages:

• Precision targeting: traditional cancer therapies often lack specificity, affecting both cancerous and healthy cells, leading to side effects and limited efficacy. In contrast, STRIs are highly selective, specifically targeting the eIF4F complex’s function within cancer cells. This precision minimizes damage to healthy tissues, potentially reducing side effects and improving patient quality of life.
• Overcoming resistance: many cancers develop resistance to traditional therapies over time. STRIs disrupt the production of multiple pathway-related proteins at the same time, making it more difficult for cancer cells to develop resistance. By directly inhibiting the translation of disease-causing proteins, STRIs offer a novel strategy to overcome resistance mechanisms.
• Broad applicability: STRIs have shown promise in a range of cancer types, including solid tumors and hematological malignancies. This versatility makes them a valuable addition to the oncology treatment arsenal, potentially benefiting a wide spectrum of cancer patients.
• Combination potential: STRIs can be used in combination with other therapies, such as immunotherapies or targeted agents, to enhance treatment outcomes. This versatility allows for tailored treatment approaches that address multiple aspects of cancer biology simultaneously.

In summary, STRIs offer a transformative approach to cancer treatment by directly targeting the eIF4F complex, disrupting cancer-driving protein translation, and providing advantages in terms of precision, resistance prevention, broad applicability, and combination potential. These characteristics position STRIs as a promising class of oncology drugs with the potential to significantly impact cancer care and improve patient outcomes.