GSPT1 (G1 To S Phase Transition 1)

In H1299 cells, TMEM106C silencing impaired compensatory mitophagy and increased apoptosis, whereas restoration of GSPT1 partially rescued the tumor-suppressive effects of TMEM106C silencing. In summary, TMEM106C promotes LUAD progression by maintaining GSPT1 expression and enhancing compensatory mitophagy, accompanied by altered Parkin ubiquitination and reduced apoptosis.

By leveraging the abundance and structural diversity of primary amines, this scalable platform expands the accessible chemical space, circumventing the complexities of de novo rational design. Ultimately, this work provides a streamlined engine for harnessing diverse E3 ligases, accelerating the development of next-generation MGDs to tackle intractable diseases.

We unveil a new experimental approach to successfully prevent treatment-resistant colorectal cancer progression by combining epigenetic modulators with a cereblon-dependent degrader of GSPT1, a regulator of protein synthesis, to normalize chromatin accessibility and induce colorectal cancer cell death. Collectively, our study identifies the integrated stress response as an inducer of epigenetic and transcriptional plasticity in colorectal cancer cells and highlights a successful approach to therapeutic intervention.

Oral administration of BMS-986458 results in dose-dependent pharmacokinetics, pharmacodynamics, and significant antitumor efficacy in mouse models of lymphoma. A potential first-in-class agent, BMS-986458, is currently being evaluated in a phase 1/2 clinical trial (NCT06090539) for patients with relapsed/refractory NHL.

Consequently, A5 exhibited enhanced antiproliferative activity compared to the BCL6 inhibitor BI3812 and the BCL6 degrader BI3802, along with induction of cell cycle arrest and apoptosis. Furthermore, A5 significantly downregulated BCL6 and GSPT1 protein levels in vivo. Thus, this study provides a solid foundation for the development of novel multitarget BCL6 degraders with improved anti-lymphoma potential.

CC-90009 exerts potent anti-JEV activity both in vitro and in vivo by inducing proteasomal degradation of the GSPT1/NS5 complex, thereby disrupting viral translation and replication. This targeted protein degradation strategy represents a novel host-directed antiviral approach with promising therapeutic potential against mosquito-borne viral encephalitis.

Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide degrade IKZF1/3 and are combined with other therapies to treat hematologic malignancies, including multiple myeloma and non-Hodgkin lymphoma. Molecular docking studies suggested that DIX-01 may form stable ternary complexes with CRBN-IKZF1 and CRBN-GSPT1, providing a structural basis for its dual-target degradation activity. Furthermore, DIX-01 significantly inhibited tumor growth in a zebrafish xenograft model transplanted with human acute myeloid leukemia cells (MV4-11), supporting its potential as a therapeutic agent for hematologic malignancies.

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.