Discovery of Potent Kinase Inhibitors with Improved Pharmacokinetics and Safety Through Structural Optimization of Dasatinib

Structural optimization of dasatinib led to the discovery of PDD-87, a potent kinase inhibitor with improved pharmacokinetics and safety. PDD-87 strongly inhibits ABL and BTK along with their key mutants, as well as SRC family kinases (IC₅₀ < 1 nM), displaying potent antiproliferative effects against several leukemia and lymphoma cell lines. In a K-562G mouse xenograft model, PDD-87 significantly reduced tumor growth in a dose-dependent manner. Compared to dasatinib, PDD-87 exhibited lower clearance, reduced volume of distribution, higher plasma exposure, and improved oral bioavailability. Metabolically, PDD-87 undergoes hydroxylation on the 2-chloro-6-methylphenyl ring, followed by sulfation, and glucuronidation. Significantly, PDD-87 shows markedly lower lung accumulation than dasatinib, suggesting a reduced risk of pulmonary toxicity. Additionally, PDD-87 was well-tolerated in mice at doses up to 200 mg/day for two weeks, with no overt toxicity. These findings support PDD-87 as a highly potent, selective kinase inhibitor with enhanced pharmacokinetics and safety, holding promise for broader clinical applications.