Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors

by Selleckchem | Sep 09 2023

The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

Comments:

BI-4020 is a novel tyrosine kinase inhibitor (TKI) that has been developed to target the epidermal growth factor receptor (EGFR) in lung tumors carrying activating mutations such as del19 or L858R. These mutations in EGFR result in the receptor becoming oncogenic and driving tumor growth. While initial responses to TKIs are often associated with significant tumor shrinkage, the effectiveness of the treatment is usually not long-lasting. Many patients experience relapse within two years of therapy, often due to the emergence of additional mutations in the EGFR kinase domain that confer resistance to TKIs.

In particular, two common resistance mutations that can occur in EGFR are T790M and C797S. Lung tumors harboring both of these mutations become resistant to currently approved EGFR TKIs, making it challenging to find effective treatment options. However, the discovery of BI-4020 provides a potential solution to this problem.

BI-4020 is a macrocyclic TKI that acts as a potent inhibitor of EGFR, including the variants carrying the resistance mutations T790M and C797S. Notably, it is designed to spare the wild-type EGFR, which is important to avoid potential toxicities associated with inhibiting the normal function of EGFR in healthy tissues.

The development of BI-4020 involved the identification of a highly selective benzimidazole compound that exhibited moderate potency. To enhance its effectiveness, the molecule was rigidified through macrocyclization, which improved its binding affinity and inhibitory activity against the target EGFR variants.

Preclinical studies using a xenograft model that mimics the cross-resistance observed in patients with EGFRdel19 T790M C797S tumors demonstrated that BI-4020 induced tumor regressions. These findings suggest that BI-4020 has the potential to overcome resistance and provide a promising therapeutic option for patients with lung tumors carrying EGFR mutations, including those with the T790M and C797S mutations.

It is important to note that the information provided here is based on a hypothetical scenario and may not reflect the latest developments in EGFR-targeted therapies. Please consult scientific literature and medical professionals for the most up-to-date and accurate information regarding specific drugs and treatments.