Trends in Pharmacological Sciences
ReviewPharmacological inhibitors of MAPK pathways
Section snippets
Target validation and status in the clinic
The most extensive activity in MAPK inhibitor development has revolved around p38, which is reflected in more than 48 patent applications from 15pharmaceutical companies [8]. The rationale for targeting p38 comes from its role as a major signal transducer responding to cellular stress stimuli such as cytokines 9, 10, 11. p38 was independently identified by multiple groups who were isolating kinases involved in cellular responses to cellular stresses such as heat shock, osmotic stress, sodium
MEK inhibitors
The development of MEK1 and MEK2 inhibitors has also progressed, although not as rapidly as the development of p38 inhibitors. These efforts have been impeded by the lack of three-dimensional structures for any members of the MEK family. Structural information is particularly important for this class of kinase inhibitors because two of these inhibitors, PD98059 and U0126 (Fig. 2), do not appear to compete with ATP and thus are likely to have a distinct binding site on MEK 5, 36. Detailed
JNK/SAPK pathway inhibitors
The JNK/SAPK MAPK pathway is also being targeted for small-molecule drug development. SP600125 (Fig. 3), has been reported to inhibit JNK2 at 100 nm in vitro and does not inhibit ERK, p38β or IκB kinase (IKK) at micromolar concentrations [50]. Although the cellular IC50 value was micromolar, the in vitro data suggest that the JNK family might be amenable to small-molecule drug discovery. The development of specific inhibitors for each family of MAPKs and inhibitors that act at different levels
Raf-1 inhibitors
A three-kinase-coupled assay was used by Glaxo Wellcome to identify potent Raf-1 inhibitors in a series of oxindoles (Fig. 3) [53]. Phenol substituents increased inhibitor potency. Several compounds with acidic pKa values were found to possess IC50 values in the low nanomolar range and blocked ERK1 and ERK2 activation in cells in the low micromolar range. A Raf-1 inhibitor that competes with ATP has also been reported by Merck and has an IC50 value of 2 nm against recombinant Raf and 0.3–2.0 μm
Concluding remarks
Less than a decade ago the kinases constituting mammalian MAPK pathways were identified through intense efforts to understand the molecular events underlying cellular responses to extracellular signals. During this decade the kinases constituting MAPK pathways have come to be appreciated as key cellular signal transducers and thus attractive targets for drug development. Successful drug development has required the demonstration that the difficulties presented by a large gene family with a
Chemical names
SB202190: phenol, 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl] SB203580: pyridine, 4-[4-(4-fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-1H-imidazol-5-yl] SB216995: pyridine, 4-[1-(cyclopropylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl] SB218655: 2-pyrimidinamine, 4-[1-(cyclopropylmethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl] SB220025: 2-pyrimidinamine, 4-[4-(4-fluorophenyl)-1-(4-piperidinyl)-1H-imidazol-5-yl] VK19911: pyridine, 4-[4-(4-fluorophenyl)-1-(4-piperidinyl)-1H-imidazol-5-yl]
Acknowledgements
We thank Ronald Doll and Bing-e Xu for thoughtful comments about the manuscript, Ronald Doll and Corey Strickland for assistance with the figures, and Dionne Ware for administrative assistance. M.H.C. acknowledges the Welch Foundation for support of work in her laboratory.
References (55)
A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
Nature
(1994)Initial sequencing of the human genome
Nature
(2001)Inhibition of p38 MAP kinase as a therapeutic strategy
Immunopharmacology
(2000)SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence
J. Pharmacol. Exp. Ther.
(2000)SAR of 4-hydroxy-piperidine and hydroxyalkyl substituted heterocycles as novel p38 map kinase inhibitors
Bioorg. Med. Chem. Lett.
(2000)- et al.
How MAP kinases are regulated
J. Biol. Chem.
(1995) Active and inactive protein kinases: structural basis for regulation
Cell
(1996)Structural analysis of receptor tyrosine kinases
Prog. Biophys. Mol. Biol.
(1999)Crystal structure of p38 mitogen-activated protein kinase
J. Biol. Chem.
(1996)The structure of mitogen-activated protein kinase p38 at 2.1-Å resolution
Proc. Natl. Acad. Sci. U. S. A.
(1997)