What question did this study set out to answer?

To design and evaluate novel inhibitors targeting KRAS-G12D mutations in pancreatic and colorectal cancers.

February 8, 2026Journal of Enzyme Inhibition and Medicinal Chemistry0 citationsOpen Access

Design, synthesis and biological evaluation of novel KRAS-G12D inhibitors

MBMohammad Hassan Baig YJYun Seong JoGhent University Global Campus SNSagar D. NaleGhent University Global Campus

Key Points

To design and evaluate novel inhibitors targeting KRAS-G12D mutations in pancreatic and colorectal cancers.
Synthesis of two novel KRAS-G12D inhibitors, GD-2 and GD-4.
Evaluation of antiproliferative activity in AGS and ASPC1 cancer cell lines.
Assessment of protein binding affinity and dissociation constants.
Mechanistic investigations to measure phospho-ERK expression.
Molecular dynamics simulations to analyze binding interactions.
Both GD-2 and GD-4 displayed strong antiproliferative activity with IC₅。 values between 0.2 and 1.8 µM.
GD-4 exhibited a significantly lower dissociation constant (Kd) of 3.18 nM compared to GD-2's 146 nM.
Both compounds significantly reduced downstream phospho-ERK expression, indicating effective inhibition.
Molecular dynamics confirmed stable binding interactions within the KRAS-G12D pocket.

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.

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