In recent years, with the successful
development of proteolysis-targeting
chimeric molecules (PROTACs), the potential of heterobifunctional
molecules to contribute to reenvisioning drug design, especially small-molecule
drugs, has been increasingly recognized. Inspired by PROTACs, diverse
heterobifunctional molecules have been reported to simultaneously
bind two or more molecules and bring them into proximity to interaction,
such as ribonuclease-recruiting, autophagy-recruiting, lysosome-recruiting,
kinase-recruiting, phosphatase-recruiting, glycosyltransferase-recruiting,
and acetyltransferase-recruiting chimeras. On the basis of the heterobifunctional
principle, more opportunities for advancing drug design by linking
potential effectors to a protein of interest (POI) have emerged. Herein,
we introduce heterobifunctional molecules other than PROTACs, summarize
the limitations of existing molecules, list the main challenges, and
propose perspectives for future research directions, providing insight
into alternative design strategies based on substrate-proximity-based
targeting.