INCB-024360

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Background

INCB024360 is a potent and selective inhibitor of IDO1 with IC50 value of 10 nM. [1]IDO means indoleamine-pyrrole 2, 3-dioxygenase. IDO is an enzyme which is encoded by the IDO1 gene. IDO is the rate-limiting and first enzyme of tryptophan which is one amino acid of human catabolism through kynurenine pathway. The decrease of L-tryptophan can cause halted growth of T cells as well as microbes. IDO belongs to immunomodulatory enzyme. It is produced by some activated macrophages and immunoregulatory cells. IDO is overexpressed in a wide range of cancer cells such as lung, prostatic, pancreatic, colorectal cancer. It is indentified to help cancer cells to escape the immune system by reducing the level of L-tryptophan in the microenvironment of cells.[2]In Hela cells, INCB024360 selectively inhibits the activity of human IDO1 with IC50 values of about 10nM. On the other hand INCB024360demonstrates little inhibition activity against human IDO1 or TDO (tryptophan 2, 3-dioxygenase). In coculture systems of human dendritic cells with allogeneic lymphocytes, INCB024360 inhibit T-cell proliferation and cytokine production and influence the viability of NK cells. INCB024360 also increase CD86 expression and promote activation T cells by DCs. In mice bearing IDO1-expressing PAN02 pancreatic tumour, ICB024360 significantly inhibit tumour growth in lymphocyte-dependent manner.[1] INCB024360 decreased plasma kynurenine levels by inhibiting the activity of IDO1 at 50 mg/kg in native C57BL/6 mice. INCB024360 also inhibit tumor growth at 100mg/kg in CT26 tumor bearing mice.[3]

[1]. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M et al: Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood, 115(17):3520-3530.
[2]. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ: Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 2003, 9(10):1269-1274.
[3]. Koblish HK, Hansbury MJ, Bowman KJ, Yang G, Neilan CL, Haley PJ, Burn TC, Waeltz P, Sparks RB, Yue EW et al: Hydroxyamidine inhibitors of indoleamine-2,3-dioxygenase potently suppress systemic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther, 9(2):489-498.