SD‐36 promotes growth inhibition and induces apoptosis via suppression of Mcl‐1 in glioma

Abstract

Glioma is one of the most commonly observed tumours, representing approximately 75% of brain tumours in the adult population. Generally, glioma therapy includes surgical resection followed by radiotherapy and chemotherapy. The transcription factor STAT3 (signal transducer and activator of transcription 3) is a promising target for the treatment of cancer and several other diseases. At nanomolar concentrations, SD‐36 induces rapid cellular degradation of STAT3 but cannot degrade other STAT proteins. The current study demonstrates the therapeutic efficacies of the STAT3 degraders SD‐36 against glioma, as well as understanding the elucidating mechanisms and identifying molecular markers that determine cell sensitivity to STAT3 degraders. Glioma cell lines possessed similar response patterns to SD‐36 but different responses to the STAT3 inhibitor Stattic. SD‐36 potently induced apoptosis in glioma cells along with a reduction in Mcl‐1 levels, which are critical for mediating the induction of apoptosis and enhancing TMZ‐induced apoptosis. Accordingly, SD‐36 sensitizes the antitumour effect of TMZ in patient‐derived xenograft. In addition, the downregulation of Mcl‐1 expression‐mediated antitumour effect of SD‐36 was analysed in cell‐derived xenograft. These observations need to be validated clinically to confirm the efficacy of STAT3 degraders in glioma.

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

“…For example, SD-36 consists of an analog of the CRBN ligand lenalidomide, a linker, and the SH2-targeting STAT3 inhibitor SI-109 [169]. It achieves tumor regression in multiple xenograft models, including acute myeloid leukemia, anaplastic large-cell lymphoma, and glioma [121,170]. SD-91 is another STAT3 degrader that is capable of achieving complete and long-lasting tumor regression in xenograft models of megakaryoblastic leukemia [171].…”

Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers

“…SD-36, the first described STAT3 PROTAC was designed and developed by the Wang lab using the cell permeable STAT3 SH2 domain and transcriptional inhibitor, SI-109, attached to an E3 ligase analogue of the CRBN ligand lenalidomide ( 320 , 322 , 323 ). SD-36 selectively degraded STAT3 ( Figure 2 ), including mutated STAT3 proteins over other STAT proteins, even though they share a conserved SH2 domain ( 323 ) in various leukemia, lymphoma ( 323 ) and glioma cell lines ( 324 ). Functionally in certain leukemia and lymphoma cell lines SD-36 inhibited STAT3 dimerization, DNA binding and target gene activity ( 323 ).…”