365 First-in-human, safety, pharmacodynamic (PD) and pharmacokinetic (PK) trial of a first-in-class dual RAF/MEK inhibitor, RO5126766, in patients with advanced or metastatic solid tumour

Soria, J-C.; Banerji, Udai; Bahleda, Ratislav; García, María Martínez; Dolly, Saoirse; Lee, L.; Rueger, Ruediger; Guarin, Ernesto; Méresse, Valérie; Albanell, Joan

doi:10.1016/s1359-6349(10)72072-3

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“…The choice of appropriate MEK and PI3K inhibitors used for development of the prototype dual inhibitor was based on a limited multifactorial analysis of optimal pharmaceutical properties, positive pre-clinical studies, structural characterization by X-ray crystallography and the presence of synthetically tractable handles that would permit facile linking of the two motifs. Following analysis of several compound structures for each target, the ATP-competitive, pan-PI3K inhibitor ZSTK474 [27] and the allosteric MEK inhibitor RO5126766 [33] were chosen as scaffolds for design of our first prototype dual inhibitor ( Figure 1 ). Like many of the allosteric MEK inhibitors, RO5126766 is an exquisitely selective and extremely potent inhibitor of MEK1 and MEK2.…”

Section: Resultsmentioning

confidence: 99%

Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor

Dort

Galbán

Wang

et al. 2015

Bioorganic & Medicinal Chemistry

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The MAP kinase (Ras/MEK/ERK) and PI3K/Akt/mTOR oncogenic signaling pathways are central regulators of KRAS-mediated transformation. Molecular reciprocity between the Ras/MEK/ERK and PI3K/Akt/mTOR pathways provides cancer cells with the ability to evade treatment when targeting only one pathway with monotherapy. Multi-kinase targeting was explored through the development of a single bivalent chemical entity by covalent linking of high-affinity MEK and PI3K inhibitors. A prototype dual-acting agent (compound 8) designed using the PI3K inhibitor ZSTK474 and the Raf/MEK inhibitor RO5126766 as scaffolds displayed high in vitro inhibition of both PI3K (IC50 = 172 nM) and MEK1 (IC50 = 473 nM). Additionally, compound 8 demonstrated significant modulation of MEK and PI3K signaling pathway activity in human A549 human lung adenocarcinoma cells and pancreatic cancer cells (PANC-1) and also decreased cellular viability in these two cell lines.

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Section: Resultsmentioning

confidence: 99%