RESUMO
Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.
Assuntos
Apoptose/fisiologia , Bibliotecas de Moléculas Pequenas/metabolismo , Canal de Ânion 2 Dependente de Voltagem/fisiologia , Proteína Killer-Antagonista Homóloga a bcl-2/fisiologia , Animais , Camundongos , Ligação Proteica , Canal de Ânion 2 Dependente de Voltagem/metabolismoRESUMO
Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.
Assuntos
Amidas/síntese química , Benzeno/química , Ureia/química , Ciclização , Estrutura MolecularRESUMO
We report on the discovery of 3-alkylthio-1,2,4-triazine dimers that are potently toxic to Plasmodium falciparum, with single digit nanomolar activity, and up to several thousand-fold lower toxicity to mammalian cells. They are equipotent against chloroquine-resistant strains of P. falciparum.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Triazinas/química , Triazinas/farmacologia , Antimaláricos/síntese química , Antimaláricos/metabolismo , Linhagem Celular , Sobrevivência Celular , Humanos , Malária Falciparum/tratamento farmacológico , Microssomos Hepáticos/metabolismo , Triazinas/síntese química , Triazinas/metabolismoRESUMO
The title mol-ecule, C(20)H(31)NO(8), has pseudo-C2 symmetry about the C-N bond, with the bis-(tert-butoxy-carbon-yl)amino group twisted from the benzene ring plane by ca 60° and the bulky tert-butoxy-carbonyl (Boc) groups are orientated away from the substituted aniline group. As part of an anti-bacterial drug discovery programme furnishing analogues of platensimycin, we unexpectedly synthesized the bis-Boc-protected aniline.
RESUMO
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
Assuntos
Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Proteínas Proto-Oncogênicas c-hck/metabolismo , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Ativação de Macrófagos/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Proto-Oncogênicas c-hck/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-hck/genética , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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 2 (RIPK2) is critical for NOD-mediated NF-κB activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-κB activation downstream of NOD engagement. Despite only delaying NF-κB activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.