Synthesis and biological characterisation of a des-aza-dasatinib tool compound

• Published in: Tetrahedron letters 2024-03, Vol.138, p.154940, Article 154940
• Main Authors: Spicer, Julie, Jose, Jiney, Lee, Woo-Jeong, Rickard, Samantha, Flanagan, Jack
• Format: Article
• Language: English
• Subjects: Dasatinib; Immunosuppression; Kinase inhibitor; Lymphocyte specific kinase
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2024.154940

[Display omitted] In this work the design and synthesis of a chemical tool compound was carried out to inform studies toward selective and potent inhibitors of lymphocyte specific kinase, a member of the Src family of kinases (SFK), for the treatment of T-cell-mediated diseases. Synthesis of a thiophene-based analogue of the pan-kinase inhibitor dasatinib was achieved using a key Buchwald coupling in a highly convergent approach that avoided isolation of unstable intermediates that derailed other approaches. Biological testing showed abrogation of activity against the SFKs in biochemical assays together with an inability to suppress downstream signalling in activated Jurkat T-cells, when compared to dasatinib. Compound 8 was also found to be 4-fold less toxic than dasatinib in a cell viability assay. Non-kinase targets of kinase inhibitors have been shown to contribute to both desired and undesired activities of clinical agents, thus thiophene analogue 8 may be used as a matched pair with dasatinib in future mechanistic studies to assess the contribution of targets outside the SFK to observed activity.