TTI-2341 (EGFR Inhibitor)

A combination of molecular design, novel fluorine-based chemical synthesis, and extensive biological testing led to the identification of TTI-2341, a novel orally available brain-penetrant, second generation, covalent EGFR inhibitor. EGFR is a validated drug target in oncology, and while the use of EGFR inhibitors has been approved for some cancer applications (non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, and colorectal cancer), use in cancers of the brain has been relatively ineffective, due in part to the low level central nervous system (CNS) penetration of existing EGFR inhibitors.

Approved CNS drugs that successfully traverse the blood brain barrier (BBB) typically exhibit high cell permeability, low transporter-mediated efflux, and low non-specific protein/lipid binding. However, attempts to optimize these parameters in EGFR inhibitors have thus far yielded few candidates that accumulate therapeutic levels of unbound drug in the brain. Furthermore, CNS-targeted inhibitors belonging to the first generation class of non-covalent EGFR compounds, such as erlotinib, are limited by a reversible mechanism of inhibition and poor activity against resistance-associated mutations such as T790M in NSCLC. Second generation inhibitors address these concerns by utilizing a chemically reactive warhead to form an irreversible covalent interaction with the ATP binding pocket of the receptor. FDA-approved second generation molecules such as afatinib display markedly improved biochemical activity against both wild type and mutant EGFR, however, BBB penetration is weak, and low brain exposure remains an obstacle in the development of these covalent compounds for CNS indications. Third generation covalent EGFR inhibitors show improved selectivity and biochemical activity towards mutant EGFR, however, like second generation EGFR inhibitors, these molecules have not yet been approved for CNS indications.

The incorporation of fluorine into small molecules is known to minimize the formation of highly reactive metabolites and improve blood brain barrier penetration. Therefore, this strategy has the potential to overcome the major limitations of existing EGFR inhibitors. We have benchmarked TTI-2341 against second (afatinib) and third-generation (osimertinib) EGFR inhibitors (both approved for the treatment of NSCLC). This comparison included measurements of blood brain barrier penetration, as well as retention, and the ratio of free to bound drug in the brain. TTI-2341 exhibited higher cell permeability, enhanced BBB penetration, and more free brain exposure than afatinib and osimertinib (see Figure below).

TTI-2341 exhibited higher cell permeability, enhanced BBB penetration, and more free brain exposure than afatinib and osimertinib

Comparison of the estimated unbound brain exposure of TTI-2341 and afatinib (left graph) or osimertinib (right graph) after a single oral dose of drug. Exposure was determined by measuring the area under the curve (AUC). The results show that TTI-2341 has greater than 15-fold higher brain exposure than afatinib and 20-fold higher brain exposure than osimertinib.

Based on our preclinical results, we plan to continue to pursue internal development of TTI-2341 for the treatment of brain cancers and brain metastases while undertaking partnering discussions in parallel.


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