Over the past two decades, kinases have represented a rich source of drug targets in oncology. Since the 2001 FDA approval of imatinib, which targets the BCR-ABL gene fusion in chronic myeloid leukemia, over twenty kinase inhibitors have been approved for many cancer types. These inhibitors differ from traditional chemotherapy by more specifically targeting cancer cell killing based on aberrant kinase signal transduction pathways instead of broadly targeting rapidly dividing cells. While these advances have led to increased progression free survival for many patients, they are rarely curative, diminishing the original excitement after imatinib’s approval. This is almost always due to the eventual development of resistance from the tumor against the kinase inhibitor being used. A striking example is the use of epidermal growth factor receptor (EGFR) inhibitors to treat non small cell lung cancer (NSCLC). EGFR mutations are the second most common oncogenic driver event in NSCLC, and third-generation EGFR inhibitors such as osimertinib have changed the standard of care for these patients. However, despite the efficiency of existing EGFR inhibitors, patients will inevitably develop resistance to these drugs, and have no further therapeutic options other than chemotherapy and locally ablative therapy for eligible patients. Therefore, new strategies of kinase inhibition are needed to overcome this problem.
Here, a team of investigators from the Dana-Farber Cancer Institute has developed a novel EGFR inhibitor that acts by allosterically blocking enzyme activity. This has the potential to delay and even overcome tumor resistance in the targeted treatment of lung cancer to existing FDA-approved EGFR inhibitors, all of which act orthosterically by occluding the ATP binding site of the kinase. The team has already identified and optimized multiple novel chemical series with improved pharmacokinetic properties and brain exposure. In this project, they will generate key data to select a clinical candidate and then advance that candidate through IND-enabling toxicology studies to ultimately enable a phase I clinical study in lung cancer patients.