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Review
. 2017;24(23):2471-2495.
doi: 10.2174/0929867324666170502123114.

Major Developments in the Design of Inhibitors along the Kynurenine Pathway

Kelly R Jacobs  1 , Gloria Castellano-Gonzalez  1 , Gilles J Guillemin  2 , David B Lovejoy  2
Affiliations
Review

Major Developments in the Design of Inhibitors along the Kynurenine Pathway

Kelly R Jacobs et al. Curr Med Chem. 2017.

Abstract

Disrupted kynurenine pathway (KP) metabolism has been implicated in the progression of neurodegenerative disease, psychiatric disorders and cancer. Modulation of enzyme activity along this pathway may therefore offer potential new therapeutic strategies for these conditions. Considering their prominent positions in the KP, the enzymes indoleamine 2,3-dioxygenase, kynurenine 3-monooxygenase and kynurenine aminotransferase, appear the most attractive targets. Already, increasing interest in this pathway has led to the identification of a number of potent and selective enzyme inhibitors with promising pre-clinical data and the elucidation of several enzyme crystal structures provides scope to rationalize the molecular mechanisms of inhibitor activity. The field seems poised to yield one or more inhibitors that should find clinical utility.

Keywords: 3-dioxygenase; Kynurenine pathway; cancer; enzyme inhibitors; indoleamine 2; kynurenine 3- monooxygenase; neurodegeneration.

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Figures

Fig. (1)
Fig. (1)
Simplified diagram of the kynurenine pathway.
Fig. (2)
Fig. (2)
Chemical structures of 1-methyl tryptophan, imidazole NLG919 and the hydroxlyamidine INCM024360.
Fig. (3)
Fig. (3)
Representative structures of IDO-1 inhibitors scaffolds and TDO inhibitor LM10 which have not progressed to clinical trials.
Fig. (4)
Fig. (4)
Key KMO inhibitor structures.
Fig. (5)
Fig. (5)
KAT inhibitor structures.
Fig. (6)
Fig. (6)
KYNU and QPRT inhibitor structures.
See this image and copyright information in PMC

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References

    1. Schwarcz R., Bruno J.P., Muchowski P.J., Wu H-Q. Kynurenines in the mammalian brain: When physiology meets pathology. Nat. Rev. Neurosci. 2012;13(7):465–477. - PMC - PubMed
    1. Munn D.H., Zhou M., Attwood J.T., Bondarev I., Conway S.J., Marshall B., Brown C., Mellor A.L. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191–1193. - PubMed
    1. Uyttenhove C., Pilotte L., Théate I., Stroobant V., Colau D., Parmentier N., Boon T., Van den Eynde B.J. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 2003;9(10):1269–1274. - PubMed
    1. Koblish H.K., Hansbury M.J., Bowman K.J., Yang G., Neilan C.L., Haley P.J., Burn T.C., Waeltz P., Sparks R.B., Yue E.W., Combs A.P., Scherle P.A., Vaddi K., Fridman J.S. Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol. Cancer Ther. 2010;9(2):489–498. - PubMed
    1. Nayak A., Hao Z., Sadek R., Vahanian N., Ramsey W.J., Kennedy E., Mautino M., Link C., Bourbo P., Dobbins R., Adams K., Diamond A., Marshall L., Munn D.H., Janik J., Khleif S.N. A Phase I study of NLG919 for adult patients with recurrent advanced solid tumors. J. Immunother. Cancer. 2014;2(Suppl. 3):250–P250.

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