A single molecule was edited into two, each targeting only one of its original two targets.

Drugs that destroy harmful proteins inside cells often grab the wrong targets by mistake. Researchers wanted to fix a dual-acting molecule, LLC0424, which accidentally targets two distinct proteins: NSD2 and GSPT1. To solve this, they used molecular editing to tweak its chemical structure. This chemical fine-tuning created two different, highly specific molecules. One new molecule, called 424-ND, works as a PROTAC that cleanly destroys NSD2 through cellular cleanup machinery called CRBN and the proteasome, shutting down androgen receptor signaling in prostate cancer cells. The other molecule, 424-GD, acts as a molecular glue that selectively destroys only GSPT1, activating key stress response markers named ATF4 and ATF3. Changing the molecules' physical shapes shifted how they bind their targets, showing that tiny chemical edits can direct drugs to destroy only the exact proteins intended.

Why it matters

This work gives researchers a method to turn a promiscuous protein degrader into two precise tools, each targeting a single protein. That matters because off-target degradation can cause side effects in therapies and confound experiments. By showing how to control selectivity, it opens a path to cleaner chemical probes and safer drugs.

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