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.
Wu et al. (Thu,) studied this question.
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