9 research outputs found
(3R,5S,7as)-(3,5-bis(4-Fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol: A Novel Neuroprotective Agent
Compounds that interact with microtubules, such as paclitaxel, have been shown to possess protective properties against β-amyloid (Aβ)-induced neurodegeneration associated with Alzheimer's disease. In this work, the novel agent (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol was investigated for effectiveness in protecting neurons against several toxic stimuli and its interaction with the microtubule network. Exposure of neuronal cultures to Aβ peptide in the presence of 5 nM (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol resulted in a 50% increase in survival. Neuronal cultures treated with other toxic stimuli such as staurosporine, thapsigargin, paraquat and H2O2 showed significantly enhanced survival in the presence of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol. Microtubule binding and tubulin assembly studies revealed differences compared to paclitaxel, but confirmed the interaction of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol with microtubules. Furthermore, in vitro studies using bovine brain microvessel endothelial cells experiments suggest that (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol can readily cross the blood-brain barrier in a passive manner
Pyrazinetetracarboxamide: A Duplex Ligand for Palladium(II)
Tetraethylpyrazine-2,3,5,6-tetracarboxamide
forms a dipalladium(II) complex with acetates occupying the fourth
coordination sites of the two bound metal ions. Crystallographic results
indicate that the “duplex” dipincer has captured two
protons that serve as the counterions. The protons lie between adjacent
amide carbonyl groups with very short O···O distances
of 2.435(5) Å. In the free base, the adjacent carbonyl groups
are farther apart, averaging 3.196(3) Å. While the dipalladium(II)
complexes stack in an ordered stepwise fashion along the <i>a</i> axis, the free base molecules stack on top of each other, with each
pincer rotated by about 60° from the one below
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Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia
Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036.
Acquired resistance to ABL1 tyrosine kinase inhibitors (TKIs) through ABL1 kinase domain mutations, particularly the gatekeeper mutant T315I, is a significant problem for patients with chronic myeloid leukemia (CML). Using structure-based drug design, we developed compounds that bind to residues (Arg386/Glu282) ABL1 uses to switch between inactive and active conformations. The lead "switch-control" inhibitor, DCC-2036, potently inhibits both unphosphorylated and phosphorylated ABL1 by inducing a type II inactive conformation, and retains efficacy against the majority of clinically relevant CML-resistance mutants, including T315I. DCC-2036 inhibits BCR-ABL1(T315I)-expressing cell lines, prolongs survival in mouse models of T315I mutant CML and B-lymphoblastic leukemia, and inhibits primary patient leukemia cells expressing T315I in vitro and in vivo, supporting its clinical development in TKI-resistant Ph(+) leukemia
Conformational Control Inhibition of the BCR-ABL1 Tyrosine Kinase, Including the Gatekeeper T315I Mutant, by the Switch-Control Inhibitor DCC-2036
Discovery of 1‑(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3‑<i>d</i>]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against <i>BRAF</i> or <i>RAS</i> Mutant Tumor Cells
The
RAS-RAF-MEK-MAPK cascade is an essential signaling pathway,
with activation typically mediated through cell surface receptors.
The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic
BRAF V600E, have shown significant clinical efficacy in melanoma patients
harboring this mutation. Because of paradoxical pathway activation,
both agents were demonstrated to promote growth and metastasis of
tumor cells with <i>RAS</i> mutations in preclinical models
and are contraindicated for treatment of cancer patients with <i>BRAF</i> WT background, including patients with <i>KRAS</i> or <i>NRAS</i> mutations. In order to eliminate the issues
associated with paradoxical MAPK pathway activation and to provide
therapeutic benefit to patients with <i>RAS</i> mutant cancers,
we sought to identify a compound not only active against BRAF V600E
but also wild type BRAF and CRAF. On the basis of its superior in
vitro and in vivo profile, compound <b>13</b> was selected for
further development and is currently being
evaluated in phase I clinical studies