Table 1.

Cell line and murine studies evaluating hypoxia inducible factor compounds

Year	Author	Study design	Compound	Findings	Reference
2008	Cummins EP et al.	Murine study with mice treated with vehicle or DMOG IP for 2 days with colons excised and epithelial cells scraped and snap-frozen in liquid nitrogen. Colitis was also induced by DSS treatment and DAI was used to determine body weight, occult blood in faeces, and stool consistency/diarrhoea. Length of colon was measured	DMOG	DMOG showed stabilization of HIF-1 in epithelial-enriched colonic mucosal scrapings and increased NF-kappaB activity; DMOG rendered mice refractory for DSS-induced weight loss and DAI increases, along with less colon shortening and presence of normal faecal pellets in colon and overall reduced DSS-induced colon injury; overall levels of inflammatory markers [e.g. MPO, TNF-α, IL-6, IL-12] were lower in DMOG-treated mice; DMOG also showed accelerated recovery and less reduction in induction of colon epithelial cell apoptosis	Cummins EP, Seeballuck F, Keely SJ, et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology 2008;134[1]:156–165. doi:10.1053/j.gastro.2007.10.012
2008	Robinson A et al.	Murine study with 10 mice with TNBS-induced colitis compared to control. FG-4497 20 or 40 mg/kg IP administered day before TNBS, 4 h prior to instillation of TNBS and on the day after TNBS administration. Outcomes evaluated after administration	FG-4497	Dosing of FG-4497 20 and 40 mg/kg respectively on day −1, day 0 and day +1 attenuated initial weight loss [p < 0.05 for both], and more significantly protected weight loss with the ongoing course of recovery [p < 0.025 for both]. Mice receiving 40 mg/kg FG-4497 showed less inflammatory infiltrate, more intact epithelium, and overall preservation of tissue architecture	Robinson A, Keely S, Karhausen J, Gerich ME, Furuta GT, Colgan SP. Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition. Gastroenterology 2008;134[1]:145–155. doi:10.1053/j.gastro.2007.09.033
2013	Keely S et al.	Murine study with TNBS colitis mice treated with AKB-4924 [HIF-1 isoform-predominant PHD inhibitor] 0.3, 1 and 5 mg/kg subcutaneously. Outcomes included inflammatory signalling, HIF-mediated epithelial barrier responses, and HIF-driven innate cell activity	AKB-4924	Mice treated with AKB-4924 experienced reduced weight loss, attenuated colon shortening, reduced tissue damage and decreased DAI. Additionally, the treatment group had augmented epithelial barrier function, leading to 50-fold reduction in serum endotoxin. Reduction in serum levels of IL-1B, IL-6 and TNF-α were also noted with treatment	Keely S, Campbell EL, Baird AW, et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis. Mucosal Immunol. 2014;7[1]:114–123. doi:10.1038/mi.2013.29
2013	Gupta R et al.	Murine study with TNBS or DSS-induced colitis treated with oral TRC160334. Treatment was initiated at 2 mg/kg/day 1 day prior to induction of colitis and continued until study termination in TNBS-induced colitis mice. Treatment in DSS-induced colitis mice was 2 and 5 mg/kg/day initiated at day 5 and continued until study termination	TRC160334	In both types of induced colitis, TRC160334 reduced DAI measured at day 2 and 4 [9.9% vs 33.6% in vehicle-treated mice]. Treatment also attenuated the severity and extent of colonic damage when compared to vehicle-treated animals and histologically, a significant reduction in severity of inflammatory and necrotic changes were noted. Percentage reduction in body weights was 13.1% vs 21.6% with TRC160334 compared to placebo. Survival rate following treatment was 42% vs 18% in vehicle mice	Gupta R, Chaudhary AR, Shah BN, et al. Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor [TRC160334] ameliorates murine colitis. Clin Exp Gastroenterol. 2014;7:13–23. doi:10.2147/CEG.S51923
2015	Marks E et al.	Murine study with TNBS-induced colitis vs vehicle-treated control animals. AKB-4942 5 mg/kg was administered every 48 h IP or orally. Prevention of colitis as measured by endoscopy, histology, barrier integrity, and immune profiling as well as potential off-target effects were assessed	AKB-4924	Mice with AKB-4942 IP treatment showed recovery within 3 days and recovered weight within 4 days. Both oral and IP treatment reduced IL-1B, TNF-α, IL-12p70 and IL-6. Reduced tissue inflammation and increased mucosal barrier function were noted. Histological disease improved in TNBS mice treated with PHD inhibitor. Oral administration of AKB-4924 was noted in ileal tissue but not heart or kidney. IP administration stabilized HIF in ileum, heart and kidney	Marks E, Goggins BJ, Cardona J, et al. Oral delivery of prolyl hydroxylase inhibitor: AKB-4924 promotes localized mucosal healing in a mouse model of colitis. Inflamm Bowel Dis. 2015;21[2]:267–275. doi:10.1097/MIB.0000000000000277
2021	Kim Y et al.	Cell studies + murine study with DNBS or DSS-induced colitis treated with CG-598 or AKB-4924 orally	CG-598	Mice treated with CG-598 had amelioration of intestinal inflammation and reduction in inflammatory lesions and pro-inflammatory cytokines. Barrier function was also noted to be boosted with expression of intestinal trefoil factor, CD73, E-cadherin and mucin	Kim YI, Yi EJ, Kim YD, et al. Local Stabilization of hypoxia-inducible factor-1α controls intestinal inflammation via enhanced gut barrier function and immune regulation. Front Immunol. 2021;11:609689. doi:10.3389/fimmu.2020.609689
2021	Goggins BJ et al.	Cell studies + murine study with TNBS-induced colitis treated with GB-004 5 mg/kg IP or vehicle solution. Disease activity was measured by endoscopy and colon were excised for histological analysis	GB-004	Cell study wise, wound closure and migration was noted along with functional blockade of certain integrins. In treated murine models, mucosal healing through induced epithelial integrin expression was noted	Goggins BJ, Minahan K, Sherwin S, et al. Pharmacological HIF-1 stabilization promotes intestinal epithelial healing through regulation of α-integrin expression and function. Am J Physiol Gastrointest Liver Physiol. 2021;320[4]:G420–G438. doi:10.1152/ajpgi.00192.2020

DAI, disease activity index; DDS, dextran sulphate sodium; DMOG, dimethyloxaylglycine; IP, intraperitoneally; NF-kappaB, nuclear factor—kappaB; TNBS, 2,4,6-trinitrobenzenesulfonic acid.