(T1030-03-17) Breaking Barriers: Quinazoline-Scaffolded Kinase Inhibitors with Optimized Blood Brain Barrier Permeability to Treat CNS Malignancies

Purpose: Kinase inhibitors have transformed the treatment landscape of various cancers. Despite their therapeutic potential, modifications to enhance CNS penetration while retaining or improving target specificity and potency remain underexplored. This study aims to bridge this gap by optimizing quinazoline-based kinase inhibitors with enhanced brain penetration and providing new therapeutic options for patients with brain metastases and other CNS-related cancers, where current treatment options are limited, and outcomes remain poor.

Methods: Employing structure-based drug design, we synthesized a series of novel quinazoline analogs specifically optimized for blood-brain barrier (BBB) penetration. Thorough in silico modeling informed the design, aiming to improve BBB permeability. Synthesized molecules were subjected to different in vitro and in vivo studies to evaluate their anticancer activity and brain permeability. Parallel artificial membrane permeability (PAMPA) experiments were used to quantitatively determine BBB permeability and estimate the brain-to-plasma partition coefficient (pLogBB).

Results: Several compounds showed significant growth inhibition against CNS and Breast cancer cell lines. Compounds HA149, HA153, and HA157 showed the most potent activity. MDA-MB-468 breast cancer cell lines showed the highest sensitivity to these compounds. Compound HA149 showed the highest brain permeability, comparable to carbamazepine (Used as a positive control), underscoring its therapeutic potential against brain malignancies.

Conclusion: Through integrated CAAD, synthetic chemistry, and a comprehensive in vitro evaluation, we successfully identified promising lead compounds comprising favorable metabolic stability, selective cytotoxicity against HER2-positive and triple-negative breast cancer cell lines, and improved CNS permeability as evidenced by PAMPA and pLogBB studies.