PT-129 

PT-129 is an RPOTAC degrader targeting the NTF2 domain (protein-RNA interaction site) of G3BP1/2, which mediates the disassembly of intracellular stress granules. PT-129 can inhibit the formation of stress granules in stressed cells and disassemble existing stress granules, and can disrupt the transmission of ATF4, thereby inhibiting the proliferation of cancer cells. Stress granules (SGs) are membrane-less cytoplasmic compartments formed under stress stimuli. SGs promote the transmission of ATF4 from fibroblasts to tumor cells through a migratory effect, mediating fibroblast-related tumor growth. And G3BP1/2 is a central protein of the SGs network, and the inhibition of G3BP1/2 may reduce the stress resistance of cancer cells in the tumor microenvironment. PT-129 is composed of a target protein ligand (red part) G3BP1/2-Targeting ligand-1 (HY-170873), an E3 ligase ligand (blue part) Thalidomide 4-fluoride (HY-41547), and a PROTAC linker (black part) Amino-PEG3-C2-acid (HY-W040165); among them, the E3 ligase ligand + linker form a complex Thalidomide-NH-PEG3-propionic acid (HY-136166)^[1].

G3BP1/2, ATF4^[1]

936.98

C₄₆H₄₈N₈O₁₂S

O=C(NC1=CC=C(NC(CCOCCOCCOCCNC2=CC=CC(C(N3C(CC4)C(NC4=O)=O)=O)=C2C3=O)=O)C=C1)[C@@H](NS(=O)(CC(N5N=CC6=C5C=CC=C6)=O)=O)CC7=CC=CC=C7

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• [1]. Dong T, et al. G3BP1/2-Targeting PROTAC Disrupts Stress Granules Dependent ATF4 Migracytosis as Cancer Therapy. J Am Chem Soc. 2025 Jan 8;147(1):446-461.  [Content Brief]