Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors.
Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients.
Koblish
Holly K
HK
Preclinical Biology, Incyte Corporation, Experimental Station, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. hkoblish@incyte.com
Hansbury
Michael J
MJ
Bowman
Kevin J
KJ
Yang
Gengjie
G
Neilan
Claire L
CL
Haley
Patrick J
PJ
Burn
Timothy C
TC
Waeltz
Paul
P
Sparks
Richard B
RB
Yue
Eddy W
EW
Combs
Andrew P
AP
Scherle
Peggy A
PA
Vaddi
Kris
K
Fridman
Jordan S
JS
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology; D008198:Lymph Nodes / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014364:Tryptophan / Q000378:metabolism*
D000578:Amidines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D014364:Tryptophan