Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors.

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Buchstaller HP, Burgdorf L, Finsinger D, Stieber F, Sirrenberg C, Amendt C, Grell M, Zenke F, Krier M

Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors.

Bioorg Med Chem Lett. 2011 Apr 15;21(8):2264-9. doi: 10.1016/j.bmcl.2011.02.108. Epub 2011 Mar 1.

PubMed ID

21420298 [ View in PubMed

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Abstract

RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sorafenib	RAF proto-oncogene serine/threonine-protein kinase	IC 50 (nM)	40	N/A	N/A	Details