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optimize lead seriesevaluate external assetstriage hits before synthesisrevisit shelved programs

Real programs, organized by the problem our partners came to us with.

Optimize lead series

Off-target kinase liabilities in ibrutinib were invisible to standard preclinical screens

Ibrutinib's preclinical program relied almost exclusively on B-cell lines and murine splenocytes, where BTK dominates and EGFR, ITK, and TEC expression is negligible. Predicting ibrutinib's phenotypic response across 979 cancer cell lines places it inside the EGFR inhibitor cluster, alongside canonical EGFR inhibitors such as osimertinib. The covalent off-targets responsible for ibrutinib's clinical adverse events (atrial fibrillation, bleeding, rash) were not confirmed until five years of post-approval chemoproteomics.

Result: Modeling response across non-hematopoietic cell types would have surfaced the same off-target signal at the hit stage, years before chemoproteomics confirmed it
Triage hits before synthesis

Recovering a clinically validated MEK inhibitor from 1.9 million compounds

The ChEMBL library of 1.9 million compounds was screened by comparing functional fingerprints against two known MEK1/2 inhibitors, trametinib and cobimetinib. Mirdametinib, an MEK1/2 inhibitor the FDA approved in February 2025 for NF1-associated plexiform neurofibroma, was recovered among a group of 123 most functionally similar compounds. The nearest compound in the model's training data, RO-4987655, differs from mirdametinib by two structural modifications.

Result: Recovered a clinically validated MEK1/2 inhibitor from a 1.9 million compound library based on functional similarity alone, without in vitro testing
Triage hits before synthesis

Four wet-lab-validated hits for BRAF-V600E melanoma from a 1.9 million compound screen

2.6 billion in silico experiments were run to predict potent, cell-line-specific hits for BRAF-V600E melanoma across the 1.9 million compound ChEMBL library. Predictions were filtered for potency and cell-line specificity, and compounds with existing literature in the indication were removed. Five vendor-available compounds remained and were tested by 48-hour Annexin V live-cell microscopy at 50nM.

Result: Four of five compounds were validated in the wet lab, an 80% hit rate compared with under 5% for traditional screening
Evaluate external assets

More case studies in this category are in progress. Check back soon, or ask us directly.

Revisit shelved programs

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