Unveiling a Novel BCL-XL Degrader: Enhancing Treatment Outlook for Hematological Cancers with Reduced Toxicity

In the context of blood cancers, the evasion of programmed cell death is a key factor in the development and progression of tumors, which is often due to the overproduction of proteins that prevent cell death, such as BCL-2 and BCL-XL. Venetoclax, a drug that targets BCL-2, has been approved by the FDA for certain types of leukemia. However, the development of BCL-XL inhibitors has been challenging due to their potential to cause thrombocytopenia, a condition characterized by a low platelet count, because platelets also rely on BCL-XL for survival.

To address this issue, researchers have proposed a new strategy involving BCL-XL degraders, which aim to selectively break down the BCL-XL protein in cancer cells while sparing platelets, which have low levels of the protein responsible for degrading BCL-XL. An early version of such a degrader, DT2216, showed promise but still resulted in platelet toxicity. This was hypothesized to be due to the strong BCL-XL inhibitory properties of the degrader's 'warhead' component, which could also affect platelets.

Using an AI-driven platform, researchers have designed a new candidate molecule, NXD02, which binds weakly to BCL-XL but can still facilitate its degradation. In preclinical studies, NXD02 demonstrated a significantly weaker binding affinity to BCL-XL compared to DT2216 but was more potent in degrading the protein and inducing apoptosis in certain cells. It also showed a strong anti-proliferative effect without affecting platelet viability in vitro and had a higher drug exposure and comparable platelet toxicity profile in vivo to DT2216.

Furthermore, NXD02 displayed stronger anti-tumor activity in a mouse model and supported the potential for weekly dosing without significant body weight loss. The molecule has also undergone initial in vitro toxicity testing with no concerns raised, and ongoing in vivo safety assessments are positive, indicating NXD02 as a promising candidate for further development for the treatment of certain cancers.