DLP-201

The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr‐Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon‐alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr‐Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase‐driven diseases. It provides valuable insights and strategies that may guide the development of next‐generation therapies.

Among cytokines, interferons (IFNs) have demonstrated antitumor effects through several mechanisms, making them attractive candidates for cancer immunotherapies.However, the application of interferons in cancer treatment comes with some obstacles, such as high toxicity owing to systemic exposure and a short half-life.The mQXL138A1 fusion protein is a murine interferon alpha-1 (IFN-α-1) fused to an antimurine Syndecan-1 (CD138) antibody designed with the aim of targeted delivery of IFN-α-1 to CD138-expressing tumor cells to enhance treatment efficacy and decrease toxicity. mQXL138A1 maintained its CD138 binding properties and exhibited IFN-dependent activity in vitro. mQXL138A1 exhibited antitumor efficacy across various syngeneic mouse models and minor levels of toxicity.Tumor growth inhibition was achieved through a combination of direct tumor cell killing and a shift in the immune activation profile of the tumor microenvironment.Although this study showed that tumor-targeted IFN-α-1 had broad antitumor properties across a range of solid tumor indications, toxicities associated with systemic activity remain an issue.