PROTACs exploit tissue-specific E3 ligase expression to convert non-specific inhibitors into tumour-selective agents. This can exploit tissue-specific E3 ligase expression to convert non-specific inhibitors into tumour-selective agents, thereby reducing toxicity in non-tumour tissues like platelets.
DT2216 is a novel PROTAC molecule licensed and developed by Dialect Therapeutics. This compound has useful properties that make it useful for targeting BCL-2 family proteins, which inhibit apoptosis and show drug resistance in many solid tumour cells. Daohong Zhou, Professor and Director, Center for Innovative Drug Discovery at the University of Texas Health San Antonio, spotlighted DT2216’s potential as a cancer therapy.
ABT263 was initially developed to inhibit BCL2 and BCL-XL; however, its development was discontinued due to untargeted toxicity on platelets, which led to severe cytopenia. With this in mind, Zhou wanted to build on the technology and convert ABT263 into a PROTAC to overcome the toxicity, rescue the target, and develop a safer and better therapeutic for cancer. This led to the discovery of DT2216.
DT2216 demonstrated strong anti-tumour activity in multiple models, including T-cell lymphoma and drug-resistant paediatric liver cancer. Zhou explained that DT2216 is more potent against MOTL4 T-ALL than ABT263 with minimal toxicity to platelets. He added that DT2216’s favourable pharmacokinetic profile supports its advancement to clinical studies.
Many oncology treatments rely on combination therapy strategies. So, Zhou experimented with pairing DT2016 with chemotherapy or targeted agents such as KRAS G12C inhibitors. In combination with chemotherapy, DT2216 was very successful at reducing the tumour size and improving treatment outcomes without increased toxicity for fibrolamellar hepatocellular carcinoma. Similar results were observed with the KRAS/DT2216 combined therapy.
This year marks an important milestone for DT2216 as it has completed phase one clinical trials. Future work aims to proceed to phase two studies and explore other combination therapies.
