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New inhibitors of Exon 20 mutations

Dr Roman Thomas, University of Cologne; Dr Daniel Rauh, Technical University of Dortmund; Dr Carsten Schulz-Fademrecht, Lead Discovery Center GmbH; Dr Bert Klebl, Lead Discovery Center GmbH

Lead Discovery Center


Despite some recent successes, lung cancer therapy is still suffering from very low survival rates. This points to a high medical need to search for new drugs to improve treatment. Personalized approaches have been successfully implemented as lung cancer therapies, e.g. the clinical use of 1st generation EGFR inhibitors is considered a paradigm shift in the treatment of EGFR-dependent lung cancers. EGFR inhibitors (such as Gefitinib and Erlotinib) are considered as frontrunners in targeted oncology therapy in general. Both, Erlotinib and Gefitinib, address oncogenic EGFR, mutationally activated by either a L858R mutation in exon 21 or exon 19 deletion. However, acquired resistance to such the 1st generation inhibitors led to the generation of resistance mutant-specific 2nd and even 3rd generation inhibitors. The 3rd generation inhibitors are mutant-specific inhibitors sparing wild type activity and thereby significantly reducing adverse side effects, like skin rash. 1st to 3rd generation EGFR inhibitors are designed to inhibit L858R and/or exon 19 deletion mutants. These inhibitors are by and large inactive against a smaller subset of EGFR/Her2 mutations, the exon 20 insertion mutants. Exon 20 insertion mutations are activating and oncogenic as well. To treat this subpopulation of lung cancer patients, EGFR/Her2 inhibitors are needed which specifically inhibit this mutated receptors, ideally sparing wild type EGFR activity.


The aim of this project is to optimize previously identified lead-like inhibitors of exon 20 mutations (Her2 INS8INSAYVN, D770_N771insSVD, H773_V774insNPH, V769_D770insASV, 772_H773insPR) and turn them into lead structures with proof of concept (PoC) in vivo. Such inhibitors should provide a treatment option for lung cancer patients with EGFR/Her2 exon 20 insertion mutations, for which known EGFR/Her2-inhibitors in clinical use and under development are inactive.

Commercial Opportunity

We have generated selective covalent inhibitors of exon 20 mutated Her2 and EGFR. These are the first inhibitors to be specifically designed for the oncogenic exon 20 mutations. The aim is to address the specific need of a subpopulation of lung cancer patients (~1-2% of all cases). Our frontrunner exon 20 insertion inhibitors show activity in lung cancer xenograft models. Ongoing medchem efforts are directed to reduce inhibitory activity against wild type EGFR and Her2 to a minimum level.

Development Status

Hit-to-Lead Phase, frontrunners are active in vivo.

Patent Situation

No patent filed yet, but composition of matter application will be filed for novel chemistry.

Further Reading

Pao, W., & Chmielecki, J. (2010). Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nature Reviews Cancer, 10(11), 760-774.

A Genomics-Based Classification of Human Lung Tumors. (2013). Science Translational Medicine, 5(209), 209ra153-209ra153.