Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma

Bruton's tyrosine kinase proteolysis-targeting chimeras (BTK-PROTACs) have emerged as a promising approach to address the limitations of BTK inhibitors. However, conducting the rational discovery of orally bioavailable BTK-PROTACs presents significant challenges. In this study, dimensionality reduction analysis and model molecule validation were utilized to identify some key structural features for improving the oral absorption of BTK-PROTACs. The results were applied to optimize the newly discovered BTK-PROTACs B1 and B2. Compound C13 was discovered with improved oral bioavailability, high BTK degradation activity, and selectivity. It exhibited inhibitory effects against different hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTKPROTAC for the treatment of lymphoma, and we hope that the strategy will find wide utility.

Automated summary

In this study, dimensionality reduction analysis and model molecule validation were used to identify key structural features for improving the oral absorption of BTK-PROTACs. The newly discovered BTK-PROTACs B1 and B2 were optimized based on the results. Compound C13 with improved oral bioavailability, high BTK degradation activity, and selectivity was discovered. It showed inhibitory effects against hematologic cancer cells and attenuated the BTK-related signaling pathway. The oral administration of C13 effectively reduced BTK protein levels and suppressed tumor growth. This study led to the discovery of a new orally bioavailable BTKPROTAC for the treatment of lymphoma.