Bringing Silicon to Drugs: Modular Construction of Sila-Pharmacophores for the Development of Target Protein Degraders.

The rapid construction of chiral pharmacophores through stepwise and modular synthesis approaches presents a significant opportunity to accelerate lead compound discovery in drug development. While carbon-based chiral cores currently dominate drug molecule structures, the stepwise functionalization of sp³ carbon centers via C-H or C-X bond manipulations remains challenging. In contrast, silicon atoms offer superior functionalization capabilities with reactive Si-H or Si-X bonds, making them ideal central atoms for the modular and stepwise construction of pharmacophores. In this study, we constructed a total of 64 silicon-containing pharmacophores through efficient modular and stepwise synthesis, starting from Si-H or Si-X bonds. Screening these sila-pharmacophores for their ability to recruit protein degradation systems led to the identification of several potent sila-protein degraders (SiDs). The versatility of these SiDs was demonstrated by their successful conjugation to various small-molecule binders/inhibitors, resulting in efficient degradation of multiple target proteins and thus expanding their potential across diverse drug targets. Notably, we observed significant tumor-suppressive activity of a SiD-conjugated ALK degrader in a xenograft model using the H3122 cell line (ALK-positive), highlighting the therapeutic potential of sila-pharmacophores. These findings underscore that silicon-centered drug motifs not only offer synthetic accessibility and convenience but also enhance drug-like properties. The silicon-carbon switch strategy introduced herein provides an innovative approach to new drug motif development, highlighting its extensive potential in drug discovery and opening new avenues for chemical biology research.