Sumitomo - Model TP-1454 -Investigational Oral Pyruvate Kinase M2 Isoform (PKM2) Activator

Understanding our target
PKM2 is an important isomer of pyruvate kinase (PK), an enzyme responsible for the last step of glycolysis (the production of pyruvate and ATP).⁴⁵ PKM2 is a dynamic form of PK that tumors favor due to its ability to switch between ATP production while in the highly active tetramer form and the creation of high levels of glycolytic intermediates in the less active dimer form, providing cancer cells with the energy and building blocks needed for rapid growth.⁴⁵ The less active PKM2 dimer also provides a metabolic advantage to tumor cells over the surrounding immune cells through this metabolic activity as well as regulating key genes involved in immune suppression.⁴⁶ This link to cancer cell proliferation, metabolism, and immune suppression makes PKM2 an attractive therapeutic target.⁴⁵

Preclinical evidence
In preclinical auxotrophic models, TP-1454 has shown a reduction in tumor growth through the activation of PKM2.⁴⁴ In a colorectal cancer model, TP-1454 in combination with anti-PD1 and anti-CTLA4 therapies showed tumor regression, tumor growth inhibition, and an acceptable safety profile.⁴⁴

Clinical development
A first-in-human, phase I trial of TP-1454 is currently being conducted in advanced solid tumors.