2 research outputs found
Pyrazinetetracarboxamide: A Duplex Ligand for Palladium(II)
Tetraethylpyrazine-2,3,5,6-tetracarboxamide
forms a dipalladiumÂ(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) Ă…. In the free base, the adjacent carbonyl groups
are farther apart, averaging 3.196(3) Ă…. While the dipalladiumÂ(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
Discovery of 1‑(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)Âpyrido[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