BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux.
Autophagy 12(7):1083 (2016)
Inhibition of prosurvival BCL2 family members can induce autophagy, but the mechanism is controversial. We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1, but others have proposed they instead inhibit BECN1. Here we confirm that small molecule ...
ID: 48: Hck activation enhances colorectal tumourigenesis by facilitating alternative macrophage polarisation
Cytokine 76(1):73 (2015)
Colorectal cancer is the second most commonly diagnosed cancer worldwide, and may develop sporadically or due to chronic colitis. Macrophages are a major component of the colorectal tumour microenvironment and may be broadly classified as classically-activated (CAM) ‘inflammatory’ or a...
Targeting cell death pathways with small molecules: playing with life and death at the cellular level to treat diseases.
Future Medicinal Chemistry 7(16):2099 (2015)
Dual role of Src kinase in governing neuronal survival.
Brain research 1594:1 (2015)
Src-family kinases (SFKs) are involved in neuronal survival and their aberrant regulation contributes to neuronal death. However, how they control neuronal survival and death remains unclear.
To define the effect of inhibition of Src activity and expression on neuronal survival.
In agreement wit...
A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production.
Nature Communications 6:6442 (2015)
Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-κB and MAP kinases. Receptor interacting protein kinase...
Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.
Cell 159(7):1549 (2014)
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host imm...
Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death.
PNAS 111(42):15072 (2014)
Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Int...
Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity.
ACS Medicinal Chemistry Letters 5(10):1088 (2014)
A-1155463, a highly potent and selective BCL-XL inhibitor, was discovered through nuclear magnetic resonance (NMR) fragment screening and structure-based design. This compound is substantially more potent against BCL-XL-dependent cell lines relative to our recently reported inhibitor, WEHI-539, ...
Simplified silvestrol analogues with potent cytotoxic activity.
Chemmedchem 9(7):1556 (2014)
The complex natural products silvestrol (1) and episilvestrol (2) are inhibitors of translation initiation through binding to the DEAD-box helicase eukaryotic initiation factor 4A (eIF4A). Both compounds are potently cytotoxic to cancer cells in vitro, and 1 has demonstrated efficacy in vivo in ...
Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL.
ACS Medicinal Chemistry Letters 5(6):662 (2014)
Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirabl...
A perspective on 10-years HTS experience at the Walter and Eliza Hall Institute of Medical Research - eighteen million assays and counting.
Combinatorial Chemistry & High Throughput Scree... 17(3):241 (2014)
The Walter and Eliza Hall Institute of Medical Research (WEHI) is Australia's longest serving medical research institute. WEHI's High Throughput Screening (HTS) Facility was established in 2003 with $5 million of infrastructure funds invested by WEHI, and the Victorian State Government's Strateg...
De-novo designed library of benzoylureas as inhibitors of BCL-XL: synthesis, structural and biochemical characterization.
Journal of medicinal and pharmaceutical chemistry 57(4):1323 (2014)
The prosurvival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anticancer therapies. We present our approach based on de novo structure-based...
Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL.
Biochemical Journal 457(3):369 (2014)
The pseudokinase MLKL (mixed lineage kinase domain-like) was identified recently as an essential checkpoint in the programmed necrosis or 'necroptosis' cell death pathway. In the present study, we report the crystal structure of the human MLKL pseudokinase domain at 1.7 Å (1 Å=0.1 nm) resolution...
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.
Nature Reviews: Molecular Cell Biology 15(1):49 (2014)
The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and...
Discovery of potent and selective benzothiazole hydrazone inhibitors of Bcl-XL.
Journal of medicinal and pharmaceutical chemistry 56(13):5514 (2013)
Developing potent molecules that inhibit Bcl-2 family mediated apoptosis affords opportunities to treat cancers via reactivation of the cell death machinery. We describe the hit-to-lead development of selective Bcl-XL inhibitors originating from a high-throughput screening campaign. Small struct...
Structure-guided design of a selective BCL-X(L) inhibitor.
Nature Chemical Biology 9(6):390 (2013)
The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibitin...
Crystallization and preliminary X-ray characterization of Epstein-Barr virus BHRF1 in complex with a benzoylurea peptidomimetic.
Acta Crystallographica Section F 68(Pt 12):1521 (2012)
BHRF1 is a pro-survival Bcl-2 homologue encoded by Epstein-Barr virus (EBV) that plays a key role in preventing premature host cell death during viral infection and may contribute to the development of malignancies associated with chronic EBV infections. The anti-apoptotic action of BHRF1 is bas...
Synthesis of conformationally constrained benzoylureas as BH3-mimetics.
Organic & Biomolecular Chemistry 10(27):5230 (2012)
The design of small molecules that mimic the BH3 domain and bind to Bcl-2 proteins has emerged as a promising approach to discovering novel anti-cancer therapeutics. We reveal the design and synthesis of conformationally constrained benzoylurea scaffolds as conformational probes. Central to heli...
BACE inhibitors as potential drugs for the treatment of Alzheimer's disease: focus on bioactivity.
Recent patents on CNS drug discovery 6(2):91 (2011)
Current drug development for the treatment of Alzheimer's Disease is principally based on the amyloid cascade theory, and aims to reduce the levels of Aβ amyloid peptide in the brain. This can be achieved, either by decreasing peptide production through inhibition of β-secretase (also known as B...
Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
Journal of medicinal and pharmaceutical chemistry 54(6):1914 (2011)
ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that conta...