1. 3. Docking, physicochemistry and in vivo properties
TRYPTOPHAN 2,3-DIOXYGENASE (TDO) INHIBITORS AS ANTICANCER IMMUNOMODULATORS
Eduard Dolušić,1 Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Lionel Pochet,1 Etienne De Plaen,2 Catherine Uyttenhove,2 Benoît Van den Eynde,2 Johan Wouters,1 Bernard Masereel1 and Raphaël Frédérick1
1) Namur Medicine & Drug Innovation Center (NAMEDIC), Namur Research Institute for Life Sciences (NARILIS), University of Namur, B-5000 Namur, Belgium
2) Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium
NAMEDIC
1. Introduction
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase 1 (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoural immune resistance.1 Many human tumours constitutively express the enzyme.2 IDO1 inhibition has accordingly been an active area of research in drug development.3
Recently, our group has shown that tryptophan 2,3 dioxygenase (TDO), an unrelated hepatic enzyme also catalysing the first step of tryptophan degradation, is as well expressed in many tumours, where it prevents their rejection by means of locally depleting tryptophan.4 The complementary role of tryptophan catabolites in this process was demonstrated by others.5
We therefore set out to develop new, improved TDO inhibitors using as the starting point the only, unoptimised series previously known in the literature.6
2. Synthesis and SAR7
Scheme 3. Synthetic schemes for
linker modifications
comp. Ar
mTDO IC50 / [mM] R
306 1 12
1-Me, F
>200 22
5-Cl 20 32
6-Br 3 13
2-Me 23
5-Br 40 33
6-Me 4 14
2-Ph 24
5-Me 34
6-OMe 5 15
4-F 10 25
5-OMe 35
6-OH 6 16
4-Cl
>40 26
5-CN 36
6-CO2Me 7 18 17
4-Br 27
5-NO2 37
7-F 8
4-CN 28
5-CO2Me 38
7-Cl 9 19
4-NO2 29
5-CO2H 39
7-Br
>20
4-CO2Me 30
6-F
7-Me 11 21
5-F 31
6-Cl 41
7-OMe
Scheme 1. Synthetic schemes for (2-pyridin-3-yl)vinylarenes
Table 1. TDO inhibitory potency of analogues IC50 values tested in cells transfected with mouse TDO (mTDO)
Scheme 2. Synthetic schemes for modifications of the side chain
comp. R R'
R''
mTDO IC50 / [mM] 3 H 1 49 F
3-F-Ph 10 58 2 30 50
3-Cl-Ph
>200 59
CO2Me 42 20 51
3-Br-Ph 60
CO2H 18 43 52
3-OMe-Ph 61 44 53
3-CN-Ph 62
CH2OH 80 45 54
3-NO2-Ph 64 Ph CN
>80 46 Me
55-trans 13 65
CO2Et 47 40
56-trans 66 48 57 67
comp. X R
mTDO IC50 / [mM] 3 1 73 CN
>80 68 80 74 44 69 6 57 10
55-trans 13 75
55-cis 76 71 77 72 78
Table 2. TDO inhibitory potency of indole derivatives
with different side chains (tested as above)
Table 3. TDO inhibitory potency of indole
derivatives with different linkers (tested as above)
3. Docking, physicochemistry and in vivo properties
= LM 10
Table 5. Oral bioavailability of 30 and 58 in mice (administr. 160 mg/kg/day)8
Figure 1. View of 58 docked
inside the TDO binding cleft7
4. References
Table 4. Exp. solubility and stability for 30, 58 and 617
Munn, D. H. and Mellor, A. L., J. Clin. Invest. 2007, 117, ; Katz, J. B., et al,
Immunol. Rev. 2008, 222, ; Prendergast, G. C., Oncogene 2008, 27,
2) Uyttenhove, C., et al, Nat. Med. 2003, 9,
3) Löb, S., et al, Nat. Rev. Cancer 2009, 9, ; Macchiarulo, A., et al, Amino Acids 2009,
37, ; Liu, X., et al, Blood 2010, 115, ; Röhrig, U. F., et al, J. Med. Chem.
2010, 53, ; Dolušić, E., et al, Bioorg. Med. Chem. 2011, 19,
4) Van den Eynde, B., et al, WO , 2010.
5) Opitz, C. A., et al, Nature 2011, 478,
6) Madge, D. G., et al, Bioorg. Med. Chem. Lett. 1996, 6,
7) Dolušić, E., et al, J. Med. Chem. 2011, 54, ; Moineaux, L., et al, Eur. J. Med. Chem.
2012, doi: /j.ejmech
8) Pilotte, L., et al, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 – 2502.
This work was supported in part by FNRS-Télévie ( ).
Figure 2. Reversal of tumoural immune resistance by systemic inhibition of TDO8