Indoleamine 2,3-Dioxygenase Is the Anticancer Target for a Novel Series of Potent Naphthoquinone-Based Inhibitors

Abstract

Indoleamine 2,3-dioxygenase (IDO) is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. While small molecule inhibitors of IDO exist, there remains a dearth of high-potency compounds offering in vivo efficacy and clinical translational potential. In this study, we address this gap by defining a new class of naphthoquinone-based IDO inhibitors exemplified by the natural product menadione, which is shown in mouse tumor models to have similar antitumor activity to previously characterized IDO inhibitors. Genetic validation that IDO is the critical in vivo target is demonstrated using IDO-null mice. Elaboration of menadione to a pyranonaphthoquinone has yielded low nanomolar potency inhibitors, including new compounds which are the most potent reported to date (K i = 61-70 nM). Synthetic accessibility of this class will facilitate preclinical chemical-genetic studies as well as further optimization of pharmacological parameters for clinical translation.

Natural Product-Inspired Pyranonaphthoquinone Inhibitors of Indoleamine 2,3-Dioxygenase-1 (IDO-1)

“…[19] Moreover, tumours developing from the wild-type parental cells regressed when injected intra-tumourally with an anti-IDO siRNA. z The clinical potential of IDO-1 as a target for cancer treatment has been further exemplified by the observation that the modest IDO-1 inhibitors 1-methyltryptophan (1-MT), [20] 5-bromobrassinin, [21] and menadione [22] while failing to regress murine tumours when used as a monotherapy, nevertheless halted the progression of established tumours in vivo when used in combination with the anti-mitotic drug paclitaxel. These observations are particularly noteworthy as paclitaxel was ineffective when used alone in these studies.…”

“…These observations are particularly noteworthy as paclitaxel was ineffective when used alone in these studies. [20][21][22] Although the IDO-1 inhibitors 2,5-dihydro-L-phenylalanine, [23] 1-methyltryptophan, [24] 4-phenylimidazole, [25] and b-carbolines such as norharman [26,27] have been known for decades, it is only since the emergence of IDO-1 as a novel target for the treatment of cancer that extensive studies towards developing inhibitors of this enzyme have emerged. [13,17] An investigation concerning the inhibitory properties of 4-phenylimidazole (4-PI) [25] has witnessed the crystal structure of IDO-1 being determined, [28] along with the production of nanomolar inhibitors of IDO-1 based on the 4-PI scaffold.…”

“…Examples include brassinin, [21,41] exiguamine A, [42][43][44] plectosphaeroic acids A and B, [45] and annulin B [22,46,47] (Fig. 1).…”

“…[22] The synthetic pyranonaphthoquinones tested were amongst the most potent IDO-1 inhibitors recorded to date using an isolated enzyme assay (K i ¼ 61-70 nM), with a select few also causing minimal impact on cell viability at 100 mM after 24 h. [22] It is well established that various naphthoquinones display potent activity as IDO-1 inhibitors, [22,[42][43][44]46,47] suggesting this moiety to be a key pharmacophore and a likely indole mimetic. [22] As the pyran containing natural products annulin B [46,47] and exiguamine A [42,43] are both potent IDO-1 inhibitors, we planned on testing a series of pyranonaphthoquinone derivatives possessing both the pyran and naphthoquinone structural features of these natural products, thus extending the naphthoquinone series of novel IDO-1 inhibitors based on lead compounds from nature (Scheme 1). Our research group has a long-standing [46] interest in the synthesis of natural products possessing a pyranonaphthoquinone moiety, [48] along with their chemical modification in order to improve their respective bioactivities.…”

3-Methyl-2-Butenal

“…2 Various examples of the use of 3-methyl-2-butenal are found in the literature. This reagent has been explored for the preparation of 1,4-dihydropiridines, 3 diene adducts, 4 pyranonaphthoquinones, 5 nitropentanal pyrrole, 6 cyclization precursors, 7 and 2H-chromenes. 9…”