EGFR
October 2021
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and has a high mortality rate worldwide (reference here). The epidermal growth factor receptor (EGFR) is frequently overexpressed in NSCLC and has been studied for a long time as an anti-cancer drug target. EGFR is a receptor tyrosine kinase belonging to the epidermal growth factor family (EGF family) and functionates as a homo- or heterodimer upon activation by growth factor ligands. Antibody-based drugs and small-molecule tyrosine kinase inhibitors (TKIs) are the two main modalities that have been explored to inhibit EGFR activity.
EGFR TKIs bind to the ATP binding site of the kinase domain and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. The therapeutical efficacy of these drugs has been improved progressively through the development of a second (irreversible binders), a third (overcoming T790M-induced drug resistance), and a fourth-generation (allosteric binders to overcome both T790M and C797S resistance) of TKIs.
Around 50% of NSCLC patients have metastasis in the central nervous system (CNS). One of the challenges with TKI design is therefore to efficiently pass the blood-brain barriers (BBB). Recent studies have shown that the addition of an acryloyl group to a secondary amine can improve the overall physicochemical properties and increase BBB penetration of a drug (see example on the first-generation EGFR TKI Gefitinib here).
Imagine you have a new design idea for an EGFR TKI with an acrylamide group and you would like to gather more knowledge on the matter, such as which acrylamide-containing ligands already exist and how does this functional group typically interact with the protein, etc. The 3decision knowledge base has the ability to answer these questions quickly with the advanced search feature. Out of over 250 available EFGR structures, 3decision will quickly retrieve only the structures responding to the two queries of interest: the gene name “EGFR” - combined with a substructure search. In 30 seconds, 3decision retrieves a list of 31 EGFR structures and their ligands characterized by the acrylamide group. By opening them in the 3D Viewer you can see the 3D arrangement of the complexes. With this, you are quickly gathering instant knowledge to help you validate your design idea.
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