Targeting BTK Resistance: The Emergence of HZ-Q1060 as a Promising BTK Degrader in Preclinical Studies

Bruton's tyrosine kinase (BTK) is a key target for treating B cell lymphoma and autoimmune disorders, but drug resistance due to the BTK C481S mutation is a significant challenge. To address this, reversible BTK inhibitors were designed, although they require higher dosages that could increase adverse effects. The development of a novel BTK-PROTAC, HZ-Q1060, using the DaTProD platform, offers a potential solution to this drug resistance issue. HZ-Q1060 has been shown to be a promising candidate for clinical advancement.

The compound effectively degrades BTK in cancer cells and human peripheral blood mononuclear cells (PBMCs), with a low DC50 in Mino cells. It also targets the mutant BTK-C481S protein without affecting other kinases, reducing the risk of side effects. In vitro studies demonstrated HZ-Q1060's ability to completely inhibit the proliferation of various lymphoma cell lines at low concentrations.

In vivo, a single oral dose of HZ-Q1060 resulted in over 80% BTK degradation within 6 hours in mice, with effects lasting up to 24 hours. In a tumor model, daily oral administration of HZ-Q1060 at 3mg/kg for 14 days completely inhibited tumor growth, comparable to ibrutinib at 10mg/kg. Pharmacokinetic studies across different animal species revealed favorable properties, including a long half-life and high dose-normalized AUC.

HZ-Q1060 showed no significant inhibition of CYPs at 10 μM, suggesting a low risk of drug-drug interactions (DDI) in future combination therapies. Additionally, it did not inhibit the hERG channel, indicating a low potential for QT prolongation. Preliminary safety evaluations in animals also indicated good safety and tolerance.

In conclusion, HZ-Q1060 is a potent and selective BTK degrader with favorable ADME characteristics and in vivo efficacy, making it a strong candidate for further clinical development.