NAMEDIC

1. 3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY Eduard Dolušić,aLuc Pilotte,bLaurence Moineaux,a Pierre Larrieu,b Vincent Stroobant,b Didier Colau,bLionel Pochet,aEtienne De Plaen,bCatherine Uyttenhove,b BenoîtVan den Eynde,b Johan Wouters,aBernard Masereel,a Steve Lannersaand Raphaël Frédéricka 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, UniversitéCatholique de Louvain, B-1200 Brussels, Belgium eduard.dolusic@unamur.be 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 Scheme 1. Synthetic schemes for (2-pyridin-3-yl)vinylarenes Table 1. TDO inhibitory potency of analogues 3 - 41. IC50 values tested in cells transfected with mouse TDO (mTDO) Scheme 2. Synthetic schemes for modifications of the side chain Table 2. TDO inhibitory potency of indole derivatives with different side chains (tested as above) Table 3. TDO inhibitory potency of indole derivativeswith different linkers (tested as above) 4. References • 1) Munn, D. H. andMellor, A. L., J. Clin. Invest. 2007, 117, 1147-1154; Katz, J. B., etal,Immunol. Rev. 2008, 222, 206-221; Prendergast, G. C., Oncogene 2008, 27, 3889-3900. • 2) Uyttenhove, C., etal, Nat. Med. 2003, 9, 1269-1274. • 3) Macchiarulo, A., etal, AminoAcids2009, 37, 219-229; Liu, X., etal, Blood 2010, 115, 3520-3530; Röhrig, U. F., etal, J. Med. Chem. 2010, 53, 1172-1189; Dolušić, E., etal, Bioorg. Med. Chem. 2011, 19, 1550-1561. • 4) Van den Eynde, B., etal, WO2010008427, 2010; • 5) Opitz, C. A., etal, Nature2011, 478, 197-203; • 6) Madge, D. G., etal, Bioorg. Med. Chem. Lett. 1996, 6, 857-860. • 7) Dolušić, E., etal, J. Med. Chem. 2011, 54, 5320-5334; Moineaux, L., etal, Eur. J. Med. Chem. 2012, 54, 95-102; • 8) Pilotte, L., etal, Proc. Natl. Acad. Sci. USA 2012, 109, 2497 – 2502. • This work was supported in part by FNRS-Télévie (7.4.543.07). 3. Docking, physicochemistry and in vivo properties Table 4. Exp. solubility and stability for 30, 58 and 617 Figure 1. View of 58 docked inside the TDO binding cleft7 3058 = LM 10 Table 5. Oral bioavailability of 30 and 58 inmice(administr. 160 mg/kg/day)8 Figure 2. Reversal of tumoural immune resistance by systemic inhibition of TDO8