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Design, synthesis and biological evaluation of novel KRAS-G12D inhibitors
Mohammad Hassan Baig1, Yun Seong Jo1, Sagar Dattatraya Nale1
1BNJBiopharma, Incheon, Republic of Korea.
Abstract:
KRAS-G12D mutations are common drivers of pancreatic and colorectal cancers, yet effective targeted therapies remain limited. This study describes the design, synthesis, and biological evaluation of two novel KRAS-G12D inhibitors, GD-2 and GD-4. Both compounds exhibited strong antiproliferative activity in AGS and ASPC1 cancer cell lines, with IC₅。 values ranging from 0.2 to 1.8 µM. The protein binding assay also demonstrated high affinity for KRAS-G12D, with dissociation constants (Kd) of 146 nM for GD-2 and 3.18 nM for GD-4. Mechanistic investigations revealed that both compounds significantly reduced downstream, as evidenced by a clear decrease in phospho-ERK expression. Additionally, molecular dynamics simulations confirmed stable binding interactions within the KRAS-G12D pocket. Collectively, these findings identify GD-2 and GD-4 as promising therapeutic candidates for KRAS-G12D-driven cancers.
Insights
Two new inhibitors, GD-2 and GD-4, show potent activity against KRAS-G12D mutations common in pancreatic and colorectal cancers. These compounds effectively inhibit cancer cell growth and downstream signaling, offering promising therapeutic potential.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- KRAS-G12D mutations are key drivers in pancreatic and colorectal cancers.
- Targeted therapies for KRAS-G12D-driven malignancies are currently limited.
Purpose of the Study:
- To design, synthesize, and evaluate novel inhibitors targeting KRAS-G12D.
- To assess the antiproliferative and binding activities of GD-2 and GD-4.
Main Methods:
- Chemical synthesis of GD-2 and GD-4.
- In vitro antiproliferative assays using AGS and ASPC1 cancer cell lines.
- Protein binding assays and molecular dynamics simulations.
- Western blot analysis for phospho-ERK expression.
Main Results:
- GD-2 and GD-4 demonstrated significant antiproliferative effects (IC50: 0.2–1.8 µM).
- High affinity for KRAS-G12D was observed (Kd: 146 nM for GD-2, 3.18 nM for GD-4).
- Compounds reduced downstream signaling, indicated by decreased phospho-ERK levels.
- Molecular dynamics confirmed stable binding within the KRAS-G12D pocket.
Conclusions:
- GD-2 and GD-4 are effective inhibitors of KRAS-G12D.
- These novel compounds represent promising therapeutic candidates for KRAS-G12D-driven cancers.
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