Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011;11(7):800-9.
doi: 10.2174/156802611795165052.

Chiral kinase inhibitors

Jian-kang Jiang  1 , Min Shen, Craig J Thomas, Mathew B Boxer
Affiliations
Review

Chiral kinase inhibitors

Jian-kang Jiang et al. Curr Top Med Chem. 2011.

Abstract

Small molecule kinase inhibitors are important tools for studying cellular signaling pathways, phenotypes and are, occasionally, useful clinical agents. With stereochemistry pervasive throughout the molecules of life it is no surprise that a single stereocenter can bestow a ligand with distinct binding affinities to various protein targets. While the majority of small molecule kinase inhibitors reported to date are achiral, a number of asymmetric compounds show great utility as tools for probing kinase-associated biomolecular events as well as promising therapeutic leads. The mechanism by which chirality is introduced varies but includes screening of chiral libraries, incorporation of chiral centers during optimization efforts and the rational installation of a chiral moiety as guided by structural and modeling efforts. Here we discuss several advanced chiral small molecule kinase inhibitors where stereochemistry plays an important role in terms of potency and selectivity.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Chemical structures of the well studied kinase inhibitors staurosporine, imatinib and sorafenib.
Figure 2
Figure 2
Chemical structures of PH-797804 and a reproduction of the X-ray structure of PH-797804 bound to p38α (PDB:3HLL).
Figure 3
Figure 3
Chemical structures showing the progression of chloropyridine 1 to A-443654 and reproductions and overlay of the X-ray structures of A-443654 bound to PKA (PDB:2JDS)(cyan colored structure) and AKT2 (PDB:2JDR)(purple colored structure). Note; residue numbering reflects PKA structure.
Figure 4
Figure 4
Chemical structures showing the progression of a lead AKT inhibitor 2 and the optimized 3 and a reproduction of the X-ray structure of 3 bound to PKA (PDB:2GU8).
Figure 5
Figure 5
Chemical structure of FR148083 and a reproduction of the X-ray structure of FR148083 bound to ERK2 (PDB:2E14).
Figure 6
Figure 6
Chemical structures showing the progression of a lead ERK2 inhibitor 4 to 7 and a reproduction of the X-ray structure of 6 bound to ERK2 (PDB:2OJJ).
Figure 7
Figure 7
Chemical structure of CP-690,550 and a reproduction of the X-ray structure of CP-690,550 bound to JAK1 (PDB:3EYG).
Figure 8
Figure 8
Chemical structures showing the progression of the lead TrkA inhibitor 11 to 14.
Figure 9
Figure 9
Chemical structures showing the progression of the lead TrkA inhibitor 16 to AZ-23.
See this image and copyright information in PMC

References

    1. Biot JB. Me'moire sur les rotations que certaines substances impriment aux axes de polarisation des rayons lumineux.'. Memoires de l'Academie des Sciences. 1818;Vol. II:41–136.
    1. Dubos R. Louis Pasteur: Free Lance of Science. Boston, MA: Little, Brown and Co.; 1950.
    1. Meijer EW. Jacobus Henricus van 't Hoff; Hundred years of impact on stereochemistry in the Netherlands. Angew. Chem. Int. Ed. 2001;40:3783–3789. - PubMed

    1. See following reference and references therein: Emil Fischer Kunz H. Unequalled classicist, master of organic chemistry research, and inspired trailblazer of biological chemistry. Angew. Chem. Int. Ed. 2002;41:4439–4451.

    1. Fischer E. Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges. 1894;27:2985–2993.

Publication types

MeSH terms