STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

A practical "preTACs-cytoblot" platform accelerates the streamlined development of PROTAC-based protein degraders.

With the growing importance of PROTAC-mediated protein degradation in drug discovery, robust synthetic methodologies and rapid screening assays are urgently needed. By harnessing the improved alkene hydroazidation reaction, we developed a novel strategy to introduce azido groups into the linker-E3 ligand conjugates and effectively created a range of prepacked terminal azide-labeled "preTACs" as PROTAC toolkit building blocks. Moreover, we demonstrated that preTACs are ready to conjugate to ligands targeting a protein of interest to generate libraries of chimeric degraders, which are subsequently screened for effective protein degradation directly from cultured cells with a cytoblot assay. Our study exemplifies that this practical "preTACs-cytoblot" platform allows efficient PROTAC assembly and rapid activity assessments. It may help industrial and academic investigators to accelerate their streamlined development of PROTAC-based protein degraders.

Structure-based rational design enables efficient discovery of a new selective and potent AKT PROTAC degrader.

AKT and associated signaling pathways have been recognized as promising therapeutic targets for decades, and growing evidence indicates that inhibition or degradation of cellular AKT are viable strategies to treat cancer. Guided by an in silico modeling approach for rational linker design and based on our previous work in this field, we herein efficiently synthesized a small group of cereblon-recruiting AKT PROTAC molecules and identified a highly potent AKT degrader B4. Compared to the existing AKT degraders, B4 has a structurally unique AKT targeting warhead derived from the pyrazole-furan conjugated piperidine derivatives. It induces selective degradation of all three isoforms of AKT and exhibits efficacious anti-proliferation against several human hematological cancers. Notably, B4 demonstrates potent inhibition of AKT downstream signaling superior to its parental inhibitor. Together with its active analogs, B4 expands the arsenal of AKT chemical degraders as a valuable probe to uncover AKTs new functions and as a potential drug candidate to treat cancer.

One therapeutic approach for triple-negative breast cancer: Checkpoint kinase 1 inhibitor AZD7762 combination with neoadjuvant carboplatin.

Carboplatin treatment is associated with potential benefits in practice in the neoadjuvant chemotherapy for Triple-negative breast cancer (TNBC) patients. In order to enhance its anti-tumor effects, new concepts for successful combination therapy are needed. Here, we interestingly found that the combination treatment of carboplatin with the Chk1 inhibitor AZD7762 synergistically inhibits TNBC cell growth in multiple TNBC cell lines in vitro. Mechanistically, we proved that prolonged carboplatin-treated induce cell mitotic arrest, and cells would fail to initiate the G2-M transition following the inhibition of the Chk1 pathway, leading to accumulation of DNA lesions. With this drug-in-combination treatment, the incidence of mitotic catastrophes including spindle multipolarity and cytokinesis failure is remarkably enhanced, which subsequently drives tumor cells multinucleation, polyploidization and apoptosis. Thus, our findings not only propose Chk1 as a therapeutic target for combination therapy with DNA-damaging agents such as carboplatin in TNBC, but also highlight that the induction of mitotic catastrophe could be considered as an alternative strategy for TNBC therapy.