Discovery of potent kinase inhibitors with improved pharmacokinetics and safety potentials through structural optimization of dasatinib

Background: Dasatinib exhibits broad therapeutic potentials for several diseases; however, its clinical application is limited by safety concerns and unfavorable pharmacokinetics.

Methods: Structural optimization of dasatinib yielded PDD-87. Preclinical studies evaluated kinase inhibition, antiproliferative activity in leukemia and lymphoma cell lines, antitumor effects in a xenograft model, pharmacokinetics and metabolism in vitro and in rodents, and exploratory safety in mice.

Results: Here we show that PDD-87 strongly inhibits ABL and Btk along with their key mutants, and 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 reduces tumor growth in a dose-dependent manner. Compared to dasatinib, PDD-87 exhibits lower clearance (405 vs 989 mL/hr/kg), reduced volume of distribution (0.9 vs 2.4 mL/hr/kg), higher plasma exposure (2521 vs 190 hr*pmol/mL for oral dose), and improved oral bioavailability (18.9 vs 3.9%) in rats. PDD-87 demonstrates lower metabolic clearance than dasatinib in human, mouse, rat, and dog liver microsomes. 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. The lung/plasma ratios of Cmax and AUClast for PDD-87 are 2 and 4, respectively, compared to 12 and 22 for dasatinib. Additionally, PDD-87 is well-tolerated in mice at doses up to 200 mg/day for two weeks, with no overt toxicity.

Conclusions: PDD-87 is a highly potent, selective kinase inhibitor with improved pharmacokinetics and safety potentials, holding promise for broader clinical applications.