HealZen Therapeutics and Dr. Jia Li's team from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences presented preclinical data of novel BTK degrader HZ-Q1070 for the first time in an oral presentation at the 2023 American Association for Cancer Research (AACR) Annual Meeting.
The abstract can be found on the AACR website.

BTK
Bruton's tyrosine kinase (BTK) plays an important role in B-cell receptor (BCR) and FcR signaling pathways. Aberrant BCR signaling can lead to dysregulated B-cell activation and thus various B-cell lymphomas, autoimmune diseases, and inflammatory diseases. BTK inhibitors (BTKi) have become an important tool for treating B-cell malignancies (such as CLL, SLL, etc.) and multiple autoimmune diseases (such as RA, MS, etc.). Both covalent and non-covalent BTKi can produce resistance-causing mutations. Therefore, there is an urgent need to develop new technologies to overcome BTK mutations that cause resistance.

Protein degrader targeting chimeras (PROTACs) are a new drug development strategy that achieves sustained degradation of targets through a cyclical catalytic mechanism. Therefore, compared to traditional small molecule inhibitors, PROTAC drugs have significant advantages in addressing acquired resistance.
Q1070
Based on the protein degradation drug development platform DaTProD®, the HealZen’s R&D team and Dr. Jia Li's team from Shanghai Institute of Materia Medica jointly developed a novel structured BTK degrader candidate which shows strong degradation potent, excellent selectivity, and good pharmaceutical properties.

• The DC50 against BTKWT is as low as picomolar levels, with strong anti-tumor proliferation inhibition activity against various lymphoma cells.
• It has strong degradation activity against multiple mutant BTK proteins (C481S, C481Y, C481F, T474M), and strongly inhibits BTK-C481S mutant cell lines.
• Completely inhibits tumor growth (including BTK-C481S mutation model) in multiple xenograft models.
• It solves the problem of poor pharmacokinetics of PROTAC molecules, and has good oral bioavailability, with over 90% degradation of BTK protein lasting for more than 24 hours in vivo.
• Preclinical toxicology studies have shown good safety.

The project is currently during the research stage for IND application.