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X-ray crystallography guides PROTAC design to degrade a nuclear receptor involved in chemotherapy resistance • Preventing colorectal cancer relapse requires overcoming drug resistance driven by the nuclear receptor PXR, which lowers intracellular chemotherapy levels. • High-resolution X-ray crystallography at beamlines ID30A-3 and ID23-2 provided crucial structural insights that guided the design of the first PROTAC ligand capable of degrading PXR in vivo. • The resulting molecule, PXR PROTAC JMV7048, reduces PXR levels in cancer cells and significantly delays tumour relapse, opening a new therapeutic avenue against chemotherapy-resistant colorectal cancer.

The challenge

Colorectal cancer (CRC) is a leading cause of cancer- related morbidity and mortality worldwide, with tumour recurrence driven in part by therapy-resistant cells. A key contributor to drug resistance is the pregnane X receptor (PXR), which regulates drug-metabolising enzymes and efflux transporters, reducing intracellular levels of chemotherapeutics. Elevated PXR expression correlates with poor prognosis in CRC and other cancers.

Although PXR silencing reduces drug resistance in CRC models, the absence of effective antagonists has hindered clinical translation. This study therefore investigates a proteolysis-targeting chimera (PROTAC) strategy to eliminate PXR. Using structural guidance, the PROTAC JMV7048 [1,2] was developed by linking the selective PXR ligand JMV6845 to the CRBN ligand thalidomide via a piperazine hexanamide linker (Figure 5), addressing

Fig. 5: Rational development of the PXR PROTAC JMV7048. a) Chemical structures of the key step compounds in the PROTAC design process. b) The crystal structure of PXR with the initial ligand, JMV6845, revealed that the C-H group (red asterisk) of the imidazole ring points toward the dynamic region of the ligand-binding pocket (red arrow). c-d) The additional aminoheptyl chain

of JMV6944 extends to the outer surface of the protein, where it forms a hydrogen bond with C207.