ZJK-807: A Selective PROTAC Degrader of KRAS^G12D Overcoming Resistance in Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• KRAS^G12D mutations drive pancreatic cancer, posing significant therapeutic challenges due to KRAS undruggability.
• Acquired resistance to KRAS inhibitors, such as MRTX1133, via secondary mutations limits treatment efficacy.

Purpose of the Study:

• To develop and characterize ZJK-807, a novel cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), for selective degradation of KRAS^G12D.
• To evaluate ZJK-807's efficacy in overcoming resistance mechanisms and its therapeutic potential in preclinical models.

Main Methods:

• Design and synthesis of ZJK-807, a PROTAC linking a KRAS^G12D inhibitor to a CRBN ligand.
• In vitro assessment of KRAS^G12D degradation, mutant-specific cytotoxicity, and resistance overcoming in cancer cell lines.
• Transcriptomic analysis to elucidate ZJK-807's molecular mechanisms of action.
• In vivo evaluation of ZJK-807's anti-tumor activity and pharmacokinetics in xenograft models.

Main Results:

• ZJK-807 selectively degrades KRAS^G12D (DC₅₀ = 79.5 ± 5.4 nM) with minimal impact on wild-type KRAS or other mutants.
• ZJK-807 demonstrates potent mutant-specific cytotoxicity and overcomes resistance conferred by secondary mutations where MRTX1133 fails.
• Transcriptomic analysis reveals suppression of RAS/MAPK signaling and unique modulation of TNF signaling and ribosome biogenesis.
• In vivo studies showed ZJK-807 achieved 47% tumor growth inhibition in AsPC-1 xenografts with favorable pharmacokinetics.

Conclusions:

• ZJK-807 represents a novel CRBN-based PROTAC with potent and selective KRAS^G12D degradation capabilities.
• This approach effectively overcomes resistance associated with secondary mutations, offering a promising therapeutic strategy for KRAS^G12D-driven cancers.
• ZJK-807 establishes a groundbreaking approach for targeting resistant KRAS^G12D mutants in malignancies.