Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors

Abstract

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]­pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]­pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

Jejucarbazoles A–C, carbazole glycosides with indoleamine 2,3-dioxygenase 1 inhibitory activity fromStreptomycessp. KCB15JA151

“…S37, S38, and Table S1 †). The 18 O isotope labeling experiment of a neocarazostatin producing strain suggested the neocarazostatin biosynthetic gene cluster could synthesize the ortho-quinone type intermediate. 27 Thus, an optical rotation value of 1 and literature studies hypothesized that the absolute conguration of the alkyl chain of 1 is 10S* and 11R*.…”

“…A literature study revealed several modes of IDO1 inhibition 18,31 through an allosteric regulator, 38 heme-binder, 23 and heme-displacer. 16 Qinglin Pu et al compared the activities of the IDO1 inhibitors in clinical trials, which showed that the inhibition by the heme-displacing mode is more potent due to its larger interaction interface with IDO1 enzyme by reason of the absence of the bulky heme moiety.…”

“…16 Qinglin Pu et al compared the activities of the IDO1 inhibitors in clinical trials, which showed that the inhibition by the heme-displacing mode is more potent due to its larger interaction interface with IDO1 enzyme by reason of the absence of the bulky heme moiety. 18 Although various compounds of tryptophan or indole analogues were studied as IDO1 inhibitors, the carbazole class has not reported any inhibitory activity against IDO1 yet. 23,39 The computational docking data between compounds 1-3 and apo-IDO1 enzyme (PDB id: 6AZV) were in good accordance with the results of IDO1 inhibition assay.…”

“…Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular heme-containing enzyme that oxidizes L-tryptophan (L-Trp) to Nformyl-L-kynurenine (NFK), which initiates the rst and ratelimiting step of the kynurenine pathway. [15][16][17][18] Expression of IDO1 mediates the degradation of tryptophan and the accumulation of kynurenine that lead to local immunosuppression. 16,19 Upregulation of IDO1 was observed in several cancer types and could promote tumor cell growth.…”

“…16,19 Upregulation of IDO1 was observed in several cancer types and could promote tumor cell growth. 18,[20][21][22] IDO1 inhibition not only can terminate the immunosuppression but also increase the effectiveness of other treatments such as therapeutic vaccination, chemotherapy, or radiationtherapy. 15,16,18,23,24 Thus, inhibition of the IDO1 enzyme is an attractive pharmaceutical target.…”