The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase

Takle, Andrew K.; Bamford, Mark J.; Davies, Susannah; Davis, Robert P.; Dean, David K.; Gaiba, Alessandra; Irving, Elaine; King, Frank D.; Naylor, A.; Parr, Christopher A.; Ray, Alison M.; Reith, Alastair D.; Smith, Beverley; Staton, Penelope C.; Steadman, Jon G.A.; Stean, Tania O.; Wilson, David M.

doi:10.1016/j.bmcl.2008.06.070

Cited by 23 publications

(9 citation statements)

References 10 publications

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“…For GW5074 and ZM336372, single concentration testing indicates substantial off‐target activities (Bain et al ., 2007). For SB590885 and SB‐699393, only partial profiles have been published (Takle et al ., 2008). In another publication (Hansen et al ., 2008), a profile on 212 kinases is mentioned, unfortunately without disclosing the underlying data.…”

Section: Tool Compounds For Clinically Relevant Kinasesmentioning

confidence: 99%

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

Uitdehaag

Verkaar

Alwan

et al. 2012

British J Pharmacology

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To establish the druggability of a target, genetic validation needs to be supplemented with pharmacological validation. Pharmacological studies, especially in the kinase field, are hampered by the fact that many reference inhibitors are not fully selective for one target. Fortunately, the initial trickle of selective inhibitors released in the public domain has steadily swelled into a stream. However, rationally picking the most selective tool compound out of the increasing amounts of available inhibitors has become progressively difficult due to the lack of accurate quantitative descriptors of drug selectivity. A recently published approach, termed ‘selectivity entropy’, is an improved way of expressing selectivity as a single‐value parameter and enables rank ordering of inhibitors. We provide a guide to select the best tool compounds for pharmacological validation experiments of candidate drug targets using selectivity entropy. In addition, we recommend which inhibitors to use for studying the biology of the 20 most investigated kinases that are clinically relevant: Abl (ABL1), AKT1, ALK, Aurora A/B, CDKs, MET, CSF1R (FMS), EGFR, FLT3, ERBB2 (HER2), IKBKB (IKK2), JAK2/3, JNK1/2/3 (MAPK8/9/10), MEK1/2, PLK1, PI3Ks, p38α (MAPK14), BRAF, SRC and VEGFR2 (KDR).

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Section: Tool Compounds For Clinically Relevant Kinasesmentioning

confidence: 99%

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

Uitdehaag

Verkaar

Alwan

et al. 2012

British J Pharmacology

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“…Diarylfurans with aliphatic, aromatic or carboxamide solubilising groups were previously shown to be alternative scaffolds for the synthesis of BRAF inhibitors 14 . Consequently, we synthesized several furan analogues with our most active tricyclic pyrazole ring B.…”

Section: Resultsmentioning

confidence: 99%

“…Furan-based analogues of SB-590885, where the core imidazole ring C was replaced by furan, with a variety of solubilizing D groups have been reported as potent BRAF inhibitors 14 . We have synthesized a number of furan-amides with our tricyclic pyrazole ‘ring B’ as BRAF inhibitors ( 1l – p ), which were found to possess weaker activity against BRAF than their imidazole counterparts, but surprisingly good cellular activity (for example compound 1m has submicromolar activity in both IC 50 ppERK and GI 50 SRB assays).…”

Section: Resultsmentioning

confidence: 99%

Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

Niculescu‐Duvaz¹,

Niculescu‐Duvaz²,

Suijkerbuijk³

et al. 2010

Bioorganic & Medicinal Chemistry

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“…Of those, the furan-based derivatives (represented by SB-699393 [28 ]) show enhanced CNS penetration. Inhibitors with such a property are of particular interest because brain metastasis is common in patients with malignant melanoma and represents a significant cause of morbidity and mortality [29].…”

Section: Conformation-specific Kinase Inhibitionmentioning

confidence: 99%

Scaffold-based design of kinase inhibitors for cancer therapy

Zhang¹,

Bollag²

2010

Current Opinion in Genetics & Development

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The identification of potent, selective and CNS penetrant furan-based inhibitors of B-Raf kinase

Cited by 23 publications

References 10 publications

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

A guide to picking the most selective kinase inhibitor tool compounds for pharmacological validation of drug targets

Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds

Scaffold-based design of kinase inhibitors for cancer therapy

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