ArticleCommunications medicine2026
Discovery of potent kinase inhibitors with improved pharmacokinetics and safety potentials through structural optimization of dasatinib.
Article in Communications medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundDasatinib exhibits broad therapeutic potentials for several diseases; however, its clinical application is limited by safety concerns and unfavorable pharmacokinetics.
methodsStructural 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.
resultsHere 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.
conclusionsPDD-87 is a highly potent, selective kinase inhibitor with improved pharmacokinetics and safety potentials, holding promise for broader clinical applications.
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Registered trials
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