Proteolysis targeted chimera (PROTAC) is a rapidly developed technology in recent years, which provides the possibility for many undruggable targets, and has become the focus of protein drug researchers.
Hematologic malignancies are cancers that affect the blood, bone marrow, and lymph nodes. Some target proteins such as BCL-XL, MDM2 and MALT1 in hematological malignant diseases are also difficult to become drugs. PROTAC technology provides a new strategy for drug development of these diseases. This paper briefly summarizes the research progress of protac in T-cell lymphoma and T-cell lymphoma.
Research of Protac on T-cell Lymphoma
Bcl-2 gene (B-cell lymphoma/eukemia-2 gene) is a kind of oncogene, which can obviously inhibit apoptosis and is one of the most important oncogenes in the study of apoptosis.
Anti-apoptotic proteins such as BCL-2, BCL-XL and MCL-1 are considered to be target proteins for malignant hematological diseases to avoid apoptosis. Recently, it has been found that most cutaneous and peripheral T-cell lymphoma (TCL) cell lines, patient-derived xenografts and major patient samples depend on BCL-XL for survival. These results suggest that targeted inhibition of BCL-XL has therapeutic value in some patients with TCL. Currently available small molecular BCL-XL inhibitors fail in clinical development due to thrombocytopenia caused by targeted toxicity. To overcome this toxicity, the research team of the Department of Pharmaceutical Sciences at the University of Arkansas developed DT2216, a BCL-XL-targeted PROTAC, ligase to VHL E3 ligase for proteasome degradation. VHL ligases are chosen because platelets express low levels of VHL, indicating that they are immune to the pro-apoptotic effect of DT2216.
Through MTS analysis, immunoblotting and flow cytometry, the team tested the therapeutic potential of DT2216 on TCL cell lines and TCL xenograft mice. The results showed that DT2216 targeting BCL-XL could selectively kill BCL-XL-dependent TCL cells without obvious platelet toxicity. In addition, DT2216 combined with inhibitors targeting other anti-apoptotic BCL-2 family proteins may have a wide range of therapeutic effects on a variety of TCL types and other BCL-XL-dependent cancers.
Research of Protac on T-cell Acute Lymphoblastic Leukaemia
T-ALL is a malignant hematological disease originating from the precursors of immature T cells. Previous studies have found that T-ALL (except for early T cell precursor ALL) is dependent on BCL-XL. However, the targeted toxicity of BCL-XL specific inhibitors to thrombocytopenia limits its application in acute leukemia.
The team from the MD Anderson Cancer Center analyzed the preclinical efficacy of DT2216 in T-ALL cell lines in vitro and in vivo T-ALL patient-derived xenotransplantation (PDX) models. The results showed that T-ALL cells were functionally dependent on BCL-XL and highly sensitive to DT2216, while B-ALL mainly depended on BCL-2, is response to BCL-2 inhibitors such as ABT-199. In T-ALL PDX model, DT2216, alone, especially combined chemotherapy, can reduce the burden of leukemia and prolong the survival time. It is suggested that DT2216 targeted BCL-XL is an efficient and safe adjuvant therapy in T-ALL.