The epidermal growth factor receptor (EGFR) is a well-established target for oncology drug discovery [1]. Dysregulation of EGFR, leading to its overexpression or constant activation, results in cancers in various tissues, including breast, pancreatic, lung, and colon tissues. While EGFR-driven tumors can be treated with several approved inhibitors, treatment efficacy is often diminished by acquired resistance mutations. Thus, there is an obvious need for new EGFR inhibitors that are effective against mutated forms of EGFR [2].
In this context an original AI-based EGFR Screening Library has been developed by the Life Chemicals team in collaboration with Variational AI. This Screening Set, derived from the proprietary HTS Compound Collection of Life Chemicals, comprises a carefully selected array of over 2,500 drug-like compounds with predicted EGFR ATP-site inhibitory activity.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Compound selection by AI applying Enki™
Variational AI selected compounds from the Life Chemicals proprietary stock and tangible compound collections applying Enki™, a foundation model for kinase potency and selectivity. Used by leading biopharmaceutical companies, Enki™ is based on a novel machine learning architecture designed from the ground up for modeling pharmacological properties of small molecules, combined with a carefully filtered and curated dataset of 1.7M experimental dose-response potency data points across hundreds of kinases, as well as structure-based evaluations of 400M ligand-target pairs. Enki™ predicts experimental potency with accuracy comparable to absolute binding free energy methods.
To produce this AI-based EGFR screening library, Enki was used to predict EGFR potency, selectivity versus 74 kinase off-targets, and solubility across the entire Life Chemicals stock and tangible HTS Compound Collections. Proceeding from the predictions provided, Life Chemicals has selected over 2,500 screening compounds with an optimal combination of potency and selectivity to include:
- 516 readily-available stock compounds;
- 2010 tangible compounds to be feasibly obtained by well-proven synthetical procedures on request.
Molecular docking as a proof-of-concept
For additional data verification, molecular docking was performed in the following PDB structures: 1XKK, 3W2S, 3W32, 6VHN, and 7B85. Most of them are mutation-free structures. Standard precision ligand docking was carried out in the ATP binding site. Ligands and proteins were prepared according to standard protocols. Constraints were not set. All Rotatable Groups near the binding site were specified. The docking results confirm the results obtained by AI. Any additional MedChem filters were not used.
Please take into account that some compounds have experimentally established biological activity and these data must be of special notice when carrying out tests on cells.
Key features:
- Method: SP docking
- X-Ray data used: 1XKK, 3W2S, 3W32, 6VHN and 7B85
- Constraints: no
- Filters used: no
- Number of compounds selected: 2,526
Figure 1. Spatial structure of the binding site of the complex of EGFR kinase with the lead docking molecule F6724-4855 and three examples of virtual hit compounds.
Representative stock screening compounds from the EGFR AI-based Screening Library
Representative tangible screening compounds from the EGFR AI-based Screening Library
Reference:
- Singh D, Attri BK, Gill RK, Bariwal J. Review on EGFR Inhibitors: Critical Updates. Mini Rev Med Chem. 2016;16(14):1134-66. doi: 10.2174/1389557516666160321114917. PMID: 26996617.
- Shi K, Wang G, Pei J, Zhang J, Wang J, Ouyang L, Wang Y, Li W. Emerging strategies to overcome resistance to third-generation EGFR inhibitors. J Hematol Oncol. 2022 Jul 15;15(1):94. doi: 10.1186/s13045-022-01311-6. PMID: 35840984; PMCID: PMC9287895.