| 초록 |
Ibrutinib (Imbruvica) is one of the blockbuster drugs targeting Bruton’s tyrosine kinase (BTK), a Tec family cytoplasmic tyrosine kinase playing a crucial role in B cell malignancies. It was approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) in 2013 and 2014, respectively. However, ibrutinib is not effective for the CLL patients having C481 mutations since it is an irreversible inhibitor. As ibrutinib is also inhibiting ITK, which is essential for the T cell receptor signaling pathways, it hampers cancer immuno-combitherapy. In order to overcome these unmet needs we launched a BTK program to discover reversible BTK-non-ITK inhibitors, resulting in a lead compound more efficacious than ibrutinib in a murine xenograft model. Lead optimization status of the discovery program will be discussed. In addition, novel tetrahydroisoquinoline chemistry developed while working on the synthesis of BTK-non-ITK inhibitor will be also presented. |
