Overcoming KRAS G12C Resistance: From Prompt to Lead Compounds in 6 Hours
A single natural-language prompt drove an autonomous drug discovery campaign that identified three lead compounds targeting sotorasib-resistant KRAS G12C — compressing 4–6 weeks of traditional work into a single afternoon.
KRAS G12C is the most actionable oncogene in non-small cell lung cancer, affecting ~13% of patients. Two approved covalent inhibitors — sotorasib and adagrasib — have transformed treatment, but acquired resistance mutations (Y96D, R68S, H95Q) now limit durability of response in the majority of patients.
Identifying next-generation inhibitors that maintain potency against these resistance variants requires screening large chemical libraries against the mutant binding pocket — a process that traditionally takes weeks of computational chemist time to set up, execute, and interpret.
One natural-language prompt. No manual configuration, no scripting, no queue management.
“Discover next-generation KRAS G12C inhibitors that overcome acquired resistance mutations (PDB: 8AZX) from small molecule covalent inhibitors. Screen for selectivity against wild-type KRAS and common resistance mutants Y96D, R68S, and H95Q. Disease context: non-small cell lung cancer with sotorasib resistance. Max 300 compounds.”
Five autonomous phases, one prompt
Research & Intelligence
Target dossier from PubMed, ChEMBL, PDB. KRAS G12C biology, Switch II pocket, resistance mechanisms, 100 known actives.
Research & Intelligence
Target dossier from PubMed, ChEMBL, PDB. KRAS G12C biology, Switch II pocket, resistance mechanisms, 100 known actives.
Library Design & Acquisition
500 adagrasib-class compounds retrieved. 398 passed quality gates with 91% warhead coverage.
Library Design & Acquisition
500 adagrasib-class compounds retrieved. 398 passed quality gates with 91% warhead coverage.
Covalent Docking
1,408 conformers docked via GNINA covalent mode across 4 warhead groups with auto-classified SMARTS patterns.
Covalent Docking
1,408 conformers docked via GNINA covalent mode across 4 warhead groups with auto-classified SMARTS patterns.
Physics-Based Validation
26 top compounds rescored with MM-GBSA + 1 ns molecular dynamics to separate genuine binders from artifacts.
Physics-Based Validation
26 top compounds rescored with MM-GBSA + 1 ns molecular dynamics to separate genuine binders from artifacts.
Multi-Agent Interpretation
4 parallel agents: screening quality, binding mode, ADMET triage, and SAR synthesis.
Multi-Agent Interpretation
4 parallel agents: screening quality, binding mode, ADMET triage, and SAR synthesis.
Three expert-level decisions the platform made automatically
These domain-specific judgement calls would normally require an experienced medicinal chemist familiar with the KRAS G12C literature. They directly determined the quality of the output.
Disabled Brenk structural alerts
The Michael acceptor warhead IS the pharmacophore for covalent Cys12 engagement, not a liability
Raised MW threshold to 1,350 Da
KRAS G12C inhibitors require large, sp3-rich scaffolds to span the shallow cryptic pocket (sotorasib: 560 Da, adagrasib: 604 Da)
Reweighted scoring: 70% physics / 30% CNN
Large covalent inhibitors fall outside CNN training domains — physics-based methods are more reliable here
Campaign output
Three lead compounds identified
CPD_0038
Best physics-validated binderSlower, more selective covalent reactivity than standard acrylamide
Predicted poor oral bioavailability — requires formulation assessment or IV dosing
CPD_0035
Best overall profileFluoropyridyl aryl wing predicted to tolerate Y96D resistance mutation. No AMES flag.
Immediate candidate for biochemical IC₅₀
CPD_0042
Tri-metric convergenceStrong convergence across all three scoring methods
Commercially purchasable for immediate testing
Two dominant scaffold series
Series A
126 compoundsFluoropyridyl-quinazoline
- Chiral fluoromethyl pyrrolidine linker — sp3-rich 3D shape
- Better ligand efficiency (LE 0.23–0.29) and oral bioavailability
- Predicted more tolerant to Y96D due to compact aryl wing
- Both acrylamide and fluoroacrylamide warheads represented
Series B
108 compoundsChlorofluoronaphthalene pyridopyrimidine
- Bridged bicyclic (DABCO-type) ether linker
- Higher raw CNN affinity but lower ligand efficiency (LE 0.21–0.26)
- Extended naphthalene provides deeper P2 pocket occupation
- May clash with Y96D aspartate — resistance risk
Class-obligate vs. addressable liabilities
Class-obligate
Shared with approved drugs — accepted risks:
- Michael acceptor warheads
- Lipinski MW violations
- DILI risk
Addressable
Compound-specific — require optimization:
- Pan-CYP inhibition (planar aromatics)
- hERG risk (basic amines)
- 7 compounds AMES-positive — hard rejected
What this demonstrates
The platform didn't just run faster — it made domain-expert decisions that would normally require an experienced medicinal chemist familiar with the KRAS G12C literature.
A prioritised, tiered portfolio of lead compounds with full SAR context, ADMET profiling, resistance mutation analysis, and a concrete experimental roadmap — ready for a project team meeting the same day the campaign was launched.
Campaign report
The complete AiDDA-generated report including target intelligence, screening results, safety assessment, SAR analysis, and experimental plan.
Download PDFRun a campaign on your target
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