Yu Mi Ahn

Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF Inhibitor with Minimal Paradoxical Activation and Activity against BRAF or RAS 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 RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS 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 13 was selected for further development and is currently being evaluated in phase I clinical studies.

Switch control pocket inhibitors of p38-MAP kinase. Durable type II inhibitors that do not require binding into the canonical ATP hinge region

Switch control pocket inhibitors of p38-alpha kinase are described. Durable type II inhibitors were designed which bind to arginines (Arg67 or Arg70) that function as key residues for mediating phospho-threonine 180 dependant conformational fluxing of p38-alpha from an inactive type II state to an active type I state. Binding to Arg70 in particular led to potent inhibitors, exemplified by DP-802, which also exhibited high kinase selectivity. Binding to Arg70 obviated the requirement for binding into the ATP Hinge region. X-ray crystallography revealed that DP-802 and analogs induce an enhanced type II conformation upon binding to either the unphosphorylated or the doubly phosphorylated form of p38-alpha kinase.

A convenient method to remove ruthenium byproducts from olefin metathesis reactions using polymer-bound triphenylphosphine oxide (TPPO)

SummaryRuthenium byproducts from ring-closing metathesis reactions can be removed by refluxing the crude reaction mixture with resin-bound triphenylphosphine oxide (TPPO) in toluene or by stirring with dimethyl sulfoxide (DMSO) and silica gel at room temperature. Residual levels of ruthenium can be achieved that are as low as 0.04 μg per 5 mg of product when a combination of TPPO, DMSO, and silica gel is used. The polymer-bound TPPO retained its efficiency after being recycled six times.

Short and efficient chiral pool and RCM approach towards the synthesis of the macrocyclic core of the salicylihalamides

The macrolactone core structure of the salicylihalamides was prepared from diacetone-D-glucose and via a ring-closing metathesis reaction.