DDB1 (Damage Specific DNA Binding Protein 1)

Mouse double minute 2 homologue (MDM2) is a priority target for novel therapeutic development and combination trials. Combinations of EZH2, MDM2 inhibitors and selective inhibitors of nuclear export should be evaluated robustly preclinically and drive early clinical studies.

KDM5B upregulation was significantly negatively correlated with the survival rates in various cancer types, including thyroid, lung, esophageal and colorectal cancers. Overall, these findings establish a novel regulatory axis in cholesterol metabolism, uncover potential therapeutic vulnerabilities in ER+ breast cancer, and suggest that targeting the KDM5B could provide a strategy to curb tumor progression.

Novel protein degrader small molecules which co-opt DCAF16 to degrade BRD4 as a neosubstrate demonstrated preferential selectivity for SF3B1 mutant cancers and CLL primary patient specimens due to increased DCAF16 protein levels. In turn, this reveals the therapeutic relevance of mutant SF3B1 dysregulation of transcript untranslated regions and uncovers a novel strategy for the treatment of these important neoplasms.

Thus, we define a novel N-degron pathway that monitors replacement of myristoylation by acetylation and activates degradation of SFKs upon acetylation. This mechanism may extend to other N-terminally myristoylated proteins beyond SFKs.

Mechanistically, DCAF13 deficiency in mesenchymal cells led to PTEN accumulation, a key negative regulator of PI3K/AKT signaling, thereby suppressing proliferation and differentiation of CNC-derived cells. Our findings establish DCAF13 as a crucial regulator of craniofacial morphogenesis through its control of the PTEN-PI3K/AKT signaling axis, which orchestrates neural crest cell proliferation and differentiation.

DCAF7 is up-regulated in various tumours and correlates with poor prognosis, particularly in LIHC. High DCAF7 expression is linked to CD4+ T cell infiltration, up-regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape. DCAF7 stabilises β-catenin by enhancing GSK-3β Ser9 phosphorylation, thereby driving c-Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC. DCAF7-high tumours demonstrate therapeutic vulnerability to 17-AAG, docetaxel and CDK/GSK-3 inhibitor, revealing potential targeted treatment strategies.

The CSC-defective traits in DDB1-deficient CRC cells were rescued by p53 deficiency but not by its overexpression, indicating that the CUL4A-DDB1-mediated regulation of p53 stability may control cancer stem-like properties in CRC. In summary, our findings emphasize DDB1 as a key regulator of colorectal cancer stemness and p53 stability through its O-GlcNAcylation at Ser-764, which enhances the E3 ligase activity of the CUL4-DDB1 complex.

In addition, the use of IGF-1 in the replenishment experiment can reverse the effect of knockdown of DCAF1, suggesting that DCAF1 may promote pancreatic cancer metastasis by activating this pathway. These findings suggest that DCAF1 functions as an oncogene in pancreatic cancer, promoting cell proliferation, migration, invasion, and EMT through activation of the PTEN/PI3K/Akt signaling pathway.

Multiple myeloma is a plasma cell malignancy that is susceptible to drugs targeting protein homeostasis such as thalidomide analogues and proteasome inhibitors...As anti-myeloma activity did not associate with dephosphorylation of known DCAF1 kinase substrates, we correlated drug-induced cellular phenotypes with whole-genome CRISPR/Cas9 resistance screening to further define mechanistic activity. These studies identified B32B3 analogues as microtubular destabilising agents with potential DCAF1 kinase independent properties and in vivo efficacy in multiple myeloma and lymphoma.

Herein, we designed, synthesized and evaluated bromodomain 4 (BRD4)-targeting PROTACs (BRD4-PROTACs) that employ a well-known BRD4 inhibitor (JQ1) as a warhead and Vpr-derived peptides as the E3 ligase-binding ligands...The chemical degraders are less effective than the parent inhibitor as a latency-reversing agent (LRA). However, the low cytotoxicity of the new peptidic PROTACs allowed the compounds to be tolerated at high does, leading to potent LRA activity.

Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.

In this study, we designed SZ-2, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. SZ-2 effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.