GSPT1 (G1 To S Phase Transition 1)

Coadministration of XZ2223 with either prodrug afforded robust tumor imaging and efficient protein degradation in xenograft models, while the XZ2223/Pro-dBET6 combination further elicited in vivo antitumor efficacy with reduced systemic toxicity. This innovative platform shows potential as a dual-function approach for precision cancer therapy.

Here, we applied our recently developed single-cell lineage tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations...In addition, in an FLT3-ITD-positive AML patient-derived xenograft (PDX) mouse model, the CC-90009 and quizartinib combination showed significantly higher anti-tumor efficacy and prolonged overall survival compared to either treatment alone...Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil pre-existing transcriptional features of treatment vulnerability in hematological cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML.

Furthermore, 5g exhibited acceptable predicted ADMET properties and had an oral bioavailability of 8.91 %. These findings indicated that compound 5g was a promising starting point for the further development of EZH2 PROTACs to treat AML.

The clinical significance is emphasized, immune interactions, and oncogenic pathways of GSPT1-targeted therapies, proposing strategies to address current challenges and provide therapeutic opportunities for the application of GSPT1 degraders in precision oncology. A novel future direction is hoped to provide to enhance the treatment response of GSPT1 MGDs in clinical implications.

Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775...This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors.

This study validated the efficacy and safety of SJ6986 in treating DLBCL and discovered its role in inducing ER stress and subsequent apoptosis, offering a promising therapeutic option for DLBCL patients.

Currently, several selective GSPT1-degraders have entered clinical trials. This review summarized the research progress of various GSPT1 degraders with an emphasis on their design, activity studies and development strategy, aiming to provide valuable insights for the further development of GSPT1 degraders.

Here, we report our efforts on Structure-Activity Relationship studies around an innovative tricyclic-containing derivatives as potent and orally bioavailable GSPT1 degraders. An in vivo xenograft model study showed that one of the synthesized compounds (26) effectively suppressed NCI-N87 tumor growth, suggesting a direction in the development of novel GSPT1 degraders.

Targeted Protein Degradation (TPD) technology, in the form of CRBN-modulating molecular glues, offers numerous unprecedented therapeutic benefits as evidenced by the success of approved high-value immunomodulatory imide drugs (IMiDs) such as lenalidomide and pomalidomide. VAP-1, which is overexpressed in cirrhotic liver, was identified as the primary monoamine oxidase responsible for the conversion of ABS-752. ABS-752 is currently in clinical trials for the treatment of HCC.

These effects were validated in AML patient cells, supporting the potential of IRAK4 inhibitors to modulate c-Myc activity and enhance combinatorial therapies. This study demonstrates that IRAK4 is a therapeutic target in AML, and that combination therapies, such as with certain GSPT1-targeting CELMoDs, will be necessary to achieve maximal clinical responses.

Importantly, A2 exhibited significantly enhanced antiproliferative activity against drug-resistant AML cells compared to Gilteritinib (MV-4-11: IC50 = 1.67 ± 0.14 nM vs IC50 = 6.52 ± 1.20 nM). Furthermore, A2 with the rigid linker demonstrated improved some pharmacokinetic properties such as half-life (T1/2), which were achieved through rational design. Overall, A2 achieves concurrent degradation of these proteins by functioning as both PROTAC and molecular glue.

Degrading GSPT1 can induce apoptosis in cancer cells and reduce their viability, thus making GSPT1 a potential therapeutic target. This perspective aims to introduce the current research status of the mechanism of molecular glues targeting GSPT1, summarize the recent progress in and challenges for existing molecular glues, bifunctional degraders, and antibody-enabled molecular glues targeting GSPT1, and outline the development strategies for targeting GSPT1 in the treatment of cancer.