Dasatinib

Dasatinib is an orally available small-molecule multikinase inhibitor that potently inhibits BCR-ABL and SRC-family kinases (SRC, LCK, YES, FYN), as well as c-KIT, PDGFR-alpha and beta, and ephrin receptor kinase. ^[1] Dasatinib is approved for the treatment of patients with BCR-ABL-positive chronic myeloid leukemia (CML) resistant or intolerant to imatinib, and for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant or intolerant to imatinib. ^[1] As a second-generation tyrosine kinase inhibitor, dasatinib is one of six BCR::ABL1 tyrosine kinase inhibitors approved by the US Food and Drug Administration for CML. ^[2]

Dasatinib acts by inhibiting key proteins involved in CML development, predominantly Bcr-Abl and Src, and it shows activity in many cases where other agents bring no improvement due to resistance. ^[3] Dasatinib and other targeted therapeutic Src protein kinase inhibitors make hydrophobic contacts with catalytic spine residues and form hydrogen bonds with hinge residues connecting the small and large kinase lobes. ^[4] In the longevity context, dasatinib combined with quercetin is used as a senolytic, a class of drugs that selectively clear senescent cells by transiently disabling the senescent cell anti-apoptotic pathways that otherwise allow these cells to survive. ^{[5] [6]}

Randomized trial data in CML show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. ^[7] Dasatinib, quercetin, fisetin and navitoclax were the first senolytic drugs, discovered using a hypothesis-driven approach, and in preclinical models senolytics delay, prevent or alleviate frailty and multiple chronic disorders. ^[5] Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans, but until such studies are done it is too early for senolytics to be used outside of clinical trials. ^[5] Dasatinib plus quercetin is described among recent senolytic strategies for eliminating

Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. ^[1] All BCR::ABL1 tyrosine kinase inhibitors are associated with hematologic toxicity such as myelosuppression, with pleural effusion being an additional adverse effect specific to dasatinib. ^[2] Most adverse effects associated with dasatinib therapy are mild to moderate in severity and are usually reversible and manageable, though they can include cardiac failure, hypertension, and coronary artery disease. ^[8]