2023AACR丨Hezheng Pharmaceutical gave an oral report at the AACR annual meeting for the first time, showing the preclinical research data of the new BTK degrader HZ-Q1070-Hangzhou Hezheng Pharmaceutical Co., Ltd.

On April 17, 2023, Hezheng Medicine and Li Jia's team from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences announced the preclinical data of the new BTK degrader HZ-Q1070 in the form of an oral report for the first time at the 2023 American Association for Cancer Research (AACR) annual meeting. Relevant abstracts can be viewed on the AACR official website

BTK Bruton's tyrosine kinase (BTK) plays an important role in the B cell receptor (BCR) and FcR signaling pathways. Abnormal BCR signaling may lead to dysregulated B cell activation, leading to a variety of B cell lymphomas, autoimmune diseases, and inflammatory diseases. BTK inhibitors (BTKi) have become an important means of treating B-cell malignancies (such as CLL, SLL, etc.) and various autoimmune diseases (such as RA, MS, etc.). Currently, both covalent and non-covalent BTKi can produce drug-resistant mutations. Therefore, there is an urgent need to develop new technologies to overcome drug resistance caused by BTK mutations. HZ-Q1070 protein degradation targeting chimera (PROTAC) is a new strategy for drug development. PROTAC can achieve continuous degradation of targets through a recycling catalytic mechanism. Therefore, compared with traditional small molecule inhibitors, PROTAC drugs have significant advantages in solving acquired resistance. Based on the protein degradation drug development platform - DaTProD®, the Hezheng R&D team and the Li Jia team of the Shanghai Institute of Materia Medica jointly developed a BTK degrader with a novel structure, strong degradation, excellent selectivity, and good druggability: ●The DC50 of BTKWT is as low as the picomolar level, and it has strong anti-tumor proliferation inhibitory activity on different lymphoma cells; ●Has strong degrading activity against multiple mutant BTK proteins (C481S, C481Y, C481F, T474M) and potently inhibits BTK-C481S mutated cell lines; ●Completely inhibits tumor growth in various transplanted tumor models (including BTK-C481S mutated models); ●Solved the problem of druggability of PROTAC molecules, various oral bioavailability is good, and >90% of BTK protein is degraded in vivo for more than 24 hours; ●Preclinical toxicology tests show good safety. The project is currently in the IND application research stage.