Dasatinib — BCR-ABL/Src kinase inhibitor — FDA-approved tyrosine kinase inhibitor (CML/ALL) with investigational senolytic off-label use
Dasatinib is a potent second-generation BCR-ABL/Src/Lck/Yes/PDGFR tyrosine kinase inhibitor FDA-approved for CML and Ph+ ALL. Its senolytic activity was discovered by Kirkland and colleagues at Mayo Clinic (2015): (1) Dasatinib selectively eliminates senescent pre-adipocytes (but NOT senescent endothelial cells) by inhibiting pro-survival kinases (PDGFR, src-family kinases) that senescent cells upregulate to evade apoptosis — the Senescent Cell Anti-Apoptotic Pathways (SCAPs); (2) Quercetin (the combination partner) eliminates senescent endothelial cells and other cell types by inhibiting PI3K/AKT and Bcl-xl; (3) The D+Q combination is complementary — targeting different senescent cell populations. CRITICAL CONTEXT: Dasatinib doses used for senolytic therapy (100 mg single dose, repeated every 3–6 months) are the SAME as CML doses — this means senolytic protocols carry ALL the cardiovascular and toxicity risks of cancer chemotherapy.
Overview
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Compound Class
BCR-ABL/Src kinase inhibitor — FDA-approved tyrosine kinase inhibitor (CML/ALL) with investigational senolytic off-label use
Mechanism of Action
Dasatinib is a potent second-generation BCR-ABL/Src/Lck/Yes/PDGFR tyrosine kinase inhibitor FDA-approved for CML and Ph+ ALL. Its senolytic activity was discovered by Kirkland and colleagues at Mayo Clinic (2015): (1) Dasatinib selectively eliminates senescent pre-adipocytes (but NOT senescent endothelial cells) by inhibiting pro-survival kinases (PDGFR, src-family kinases) that senescent cells upregulate to evade apoptosis — the Senescent Cell Anti-Apoptotic Pathways (SCAPs); (2) Quercetin (the combination partner) eliminates senescent endothelial cells and other cell types by inhibiting PI3K/AKT and Bcl-xl; (3) The D+Q combination is complementary — targeting different senescent cell populations. CRITICAL CONTEXT: Dasatinib doses used for senolytic therapy (100 mg single dose, repeated every 3–6 months) are the SAME as CML doses — this means senolytic protocols carry ALL the cardiovascular and toxicity risks of cancer chemotherapy.
Regulatory Status
FDA APPROVED for CML and Ph+ ALL at 70–140 mg/day. All senolytic use is OFF-LABEL. No FDA approval for aging/senescence. Off-label senolytic use must be supervised by a physician experienced with oncological drug toxicity.
Evidence Level
C — Phase 1 first-in-human senolytic trial (Hickson et al. 2019, n=9 IPF): confirmed reduction in senescent cell burden. Phase 2 completed for IPF (NCT02715518). Phase 2 trials ongoing for Alzheimer's (UNKEPT, NCT04785300) and diabetic kidney disease. No Phase 3 senolytic data as of 2024. All senolytic dosing carries the FULL toxicity profile of a second-generation TKI.