Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors.

Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach.

P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are closely related epigenetic proteins, each containing an acetyltransferase domain and a bromodomain. Consistent with reported roles for these proteins in immune function, we find that PCAF-deficient macrophages exhibit a markedly reduced ability to produce cytokines upon stimulation with lipopolysaccharide (LPS). Investigating the potential to target this pathway pharmacologically, we show that chemical inhibition of the PCAF/GCN5 bromodomains is insufficient to recapitulate the diminished inflammatory response of PCAF-deficient immune cells.

Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia.

Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which are often refractory to conventional therapies. Many MLL-fusion partners are members of the super elongation complex (SEC), a critical regulator of transcriptional elongation, suggesting that aberrant control of this process has an important role in leukaemia induction. Here we use a global proteomic strategy to demonstrate that MLL fusions, as part of SEC and the polymerase-associated factor complex (PAFc), are associated with the BET family of acetyl-lysine recognizing, chromatin 'adaptor' proteins.

A model to identify novel targets involved in oxidative stress-induced apoptosis in human lung epithelial cells by RNA interference.

Chronic obstructive pulmonary disease (COPD) is an increasing health problem primarily associated with cigarette smoking, and one of the leading causes of morbidity and mortality worldwide. Despite recent advances in understanding the pathogenesis of the disease, overall patient outcome remains poor with limited therapeutic intervention. Chronic inflammation, an imbalance between proteolytic and anti-proteolytic activities (leading to lung parenchyma destruction) and excessive oxidative stress contribute to COPD pathophysiology.