Probing the effects of MR120 in preclinical chronic colitis: A first-in-class anti-IBD agent targeting the CCL20/CCR6 axis

Allodi, Marika; Giorgio, Carmine; Incerti, Matteo; Corradi, Domenico; Flammini, Lisa; Ballabeni, Vigilio; Barocelli, Elisabetta; Radi, Marco; Bertoni, Simona

doi:10.1016/j.ejphar.2023.175613

Cited by 7 publications

(4 citation statements)

References 22 publications

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“…(A) Sulfonamide derivative (compound 1.061) 18 and squaramide derivative (compound 1.136); 19 (B) Squaramide analog (example 1, PF-07054894); 12 (C) Aminocyclohexylsulfone derivative (compound 35); 20 (D) Benzofurane derivative (MR120). 21,22 Figure 2. From the HTS hit 1 that displays an unsubstituted ring A and a para-OCF 3 -substituted ring B to the methylazetidine-based lead series 2 with preliminary exploration of the azetidine ring, 3 and 4.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

Meyer,

Croxford,

Gnerre

et al. 2024

J. Med. Chem.

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Migration of immune cells to sites of inflammation is a critical step in the body’s response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series–cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…Overview of the different chemotypes of small-molecule CCR6 antagonists reported in patents and publications. (A) Sulfonamide derivative (compound 1.061) and squaramide derivative (compound 1.136); (B) Squaramide analog (example 1, PF-07054894); (C) Aminocyclohexylsulfone derivative (compound 35); (D) Benzofurane derivative (MR120). , …”

Section: Introductionmentioning

confidence: 99%

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

Meyer,

Croxford,

Gnerre

et al. 2024

J. Med. Chem.

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“…The apoptotic and necrotic features of UC observable macroscopically occur due to oxidative stress induced by NO along with reactive oxygen species ( Shahid et al, 2022 ). Evaluation of macroscopic damage is used as a valuable tool in the assessment of anti-ulcerative colitis activity of tested treatments ( Allodi et al, 2023 ). Amelioration of colon ulcers and bleeding by CHME and CH n HE in a dose-dependent manner as observed in the present study has exhibited the anti-ulcerative colitis effect of C. haematocephala.…”

Section: Discussionmentioning

confidence: 99%

Anti-ulcerative colitis effects of chemically characterized extracts from Calliandra haematocephala in acetic acid-induced ulcerative colitis

Rehman,

Saleem,

Raza

et al. 2024

Front. Chem.

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Background: Ulcerative colitis is a chronic immune-mediated inflammatory bowel disease that involves inflammation and ulcers of the colon and rectum. To date, no definite cure for this disease is available.Objective: The objective of the current study was to assess the effect of Calliandra haematocephala on inflammatory mediators and oxidative stress markers for the exploration of its anti-ulcerative colitis activity in rat models of acetic acid-induced ulcerative colitis.Methods: Methanolic and n-hexane extracts of areal parts of the plant were prepared by cold extraction method. Phytochemical analysis of both extracts was performed by qualitative analysis, quantitative methods, and high-performance liquid chromatography (HPLC). Prednisone at 2 mg/kg dose and plant extracts at 250, 500, and 750 mg/kg doses were given to Wistar rats for 11 days, which were given acetic acid on 8th day through the trans-rectal route for the induction of ulcerative colitis. A comparison of treatment groups was done with a normal control group and a colitis control group. To evaluate the anti-ulcerative colitis activity of Calliandra haematocephala, different parameters such as colon macroscopic damage, ulcer index, oxidative stress markers, histopathological examination, and mRNA expression of pro and anti-inflammatory mediators were evaluated. mRNA expression analysis was carried out by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR).Results: The phytochemical evaluation revealed polyphenols, flavonoids, tannins, alkaloids, and sterols in both extracts of the plant. Results of the present study exhibited that both extracts attenuated the large bowel inflammation and prevented colon ulceration at all tested doses. Macroscopic damage and ulcer scoreswere significantly decreased by both extracts. Malondialdehyde (MDA) levels and nitrite/nitrate concentrations in colon tissues were returned to normal levels while superoxide dismutase (SOD) activity was significantly improved by all doses. Histopathological examination exhibited that both extracts prevented the inflammatory changes, cellular infiltration, and colon thickening. Gene expression analysis by RT-qPCR revealed the downregulation of pro-inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) whereas the anti-inflammatory cytokines including Interleukin-4 (IL-4) and Interleukin-10 (IL-10) were found to be upregulated in treated rats.Conclusion: It was concluded based on study outcomes that methanolic and n-hexane extracts of Calliandra haematocephala exhibited anti-ulcerative colitis activity through modulation of antioxidant defense mechanisms and the immune system. In this context, C. haematocephala can be considered as a potential therapeutic approach for cure of ulcerative colitis after bioassay-directed isolation of bioactive phytochemicals and clinical evaluation.

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“…Monitoring intestinal mucositis is challenging due to the lack of validated and robust objective measures of mucositis severity, but recently new, easily measurable markers have been introduced. These include plasma citrulline, a marker of functional enterocytes [ 18 – 20 ], and chemokine (C-C motif) ligand 20 (CCL20), which is a chemokine responsible for mucosal immune regulation, being highly upregulated during mucosal inflammation at various sites to increase the recruitment of lymphocytes [ 21 – 23 ]. Additionally, regenerating islet-derived protein 3α (REG3α), an antimicrobial peptide, can be measured at high levels systemically during gastrointestinal toxicity including inflammatory bowel disease and gastrointestinal acute graft-versus-host disease [ 24 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Markers of intestinal mucositis to predict blood stream infections at the onset of fever during treatment for childhood acute leukemia

Weischendorff,

Rathe,

Petersen

et al. 2023

Leukemia

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Despite chemotherapy-induced intestinal mucositis being a main risk factor for blood stream infections (BSIs), no studies have investigated mucositis severity to predict BSI at fever onset during acute leukemia treatment. This study prospectively evaluated intestinal mucositis severity in 85 children with acute leukemia, representing 242 febrile episodes (122 with concurrent neutropenia) by measuring plasma levels of citrulline (reflecting enterocyte loss), regenerating islet-derived-protein 3α (REG3α, an intestinal antimicrobial peptide) and CCL20 (a mucosal immune regulatory chemokine) along with the general neutrophil chemo-attractants CXCL1 and CXCL8 at fever onset. BSI was documented in 14% of all febrile episodes and in 20% of the neutropenic febrile episodes. In age-, sex-, diagnosis- and neutrophil count-adjusted analyses, decreasing citrulline levels and increasing REG3α and CCL20 levels were independently associated with increased odds of BSI (OR = 1.6, 1.5 and 1.7 per halving/doubling, all p < 0.05). Additionally, higher CXCL1 and CXCL8 levels increased the odds of BSI (OR = 1.8 and 1.7 per doubling, all p < 0.0001). All three chemokines showed improved diagnostic accuracy compared to C-reactive protein and procalcitonin. These findings underline the importance of disrupted intestinal integrity as a main risk factor for BSI and suggest that objective markers for monitoring mucositis severity may help predicting BSI at fever onset.

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Probing the effects of MR120 in preclinical chronic colitis: A first-in-class anti-IBD agent targeting the CCL20/CCR6 axis

Cited by 7 publications

References 22 publications

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

Anti-ulcerative colitis effects of chemically characterized extracts from Calliandra haematocephala in acetic acid-induced ulcerative colitis

Markers of intestinal mucositis to predict blood stream infections at the onset of fever during treatment for childhood acute leukemia

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