The KRAS G12D mutation, which is prevalent in pancreatic cancer, does not generate an allosteric pocket that is targeted by inhibitors designed for the G12C mutation.

Study: Abstract 4569: D3S-003, an orally bioavailable potent and selective dual-state inhibitor targeting both GDP- and GTP-bound KRAS G12D

Scientists found that the KRAS G12D mutation in pancreatic cancer looks different from G12C, so drugs made for G12C don’t work on it. They had to invent a brand-new drug just for G12D, proving it has a different shape that can’t be targeted by old drugs.

Study: Switch II pocket inhibitor allosterically freezes KRASG12Dnucleotide-binding site and arrests the GTPase cycle.

Scientists found a drug that can latch onto the mutated KRAS G12D protein in a way that stops it from causing cancer—even though this mutation was thought to be untouchable by such drugs. This proves the mutation does have a hidden spot that can be targeted, just like other mutations.

Study: Decoding KRAS Dynamics: Exploring the Impact of Mutations and Inhibitor Binding.

The study shows that the G12D mutation in pancreatic cancer creates a different shape in the KRAS protein than G12C, so drugs made for G12C can't stick to G12D — they need a different key to unlock it.