A Novel, Orally Active Alpha 4 Integrin Antagonist, AJM300 Prevents the Development of Experimental Colitis Induced by Adoptive Transfer of IL-10 Deficient CD4+ T Cells in Mice.

Sugiura, Toshihiko; Kageyama, Shunsuke; Andou, Ayatoshi; Miyazawa, Tomoko; Ejima, Chieko; Nakayama, Akira; Dohi, Taeko; Eda, Hiroyuki

doi:10.1124/jpet.112.193946

Cited by 3 publications

(3 citation statements)

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“…Several studies have reported the efficacy of this small molecule in animal models of IBD. A manuscript was submitted and later withdrawn as the authors did not comply with journal requirements for publishing the molecular structure 86 . Similarly, the results of a randomized, double-blind, placebo controlled trial in Japanese patients with active CD was presented during the Digestive Diseases Week meeting in 2009 87 AJM 300 was safe and well tolerated and showed a statistically significant improvement in clinical response rate in patients with moderately active UC.…”

Section: New Leukocyte Integrin Antagonists For Ibdmentioning

confidence: 99%

Integrin-based therapeutics: biological basis, clinical use and new drugs

Ley

Rivera–Nieves

Sandborn

et al. 2016

Nat Rev Drug Discov

342

296

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Integrins are activatable adhesion and signaling molecules. Of the 24 known human integrins, three are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules. The platelet αIIbβ3 integrin is targeted by Abciximab, Eptifibatide and Tirofiban, all with indications for preventing thrombotic complications after percutaneous coronary interventions. The lymphocyte α4β1 and α4β7 integrins are targeted by Natalizumab with indications in multiple sclerosis and Crohn’s disease. Although efficacious, use of this antibody is limited by a rare but serious complication, progressive multifocal leukoencephalopathy. Vedolizumab is an antibody to a combinatorial epitope in α4β7 that is approved for use in patients with Crohn’s disease or ulcerative colitis in the United States, Canada and Europe. Progressive multifocal leukoencephalopathy has not been observed in the clinical trials or clinical use of vedolizumab. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7) and MAdCAM-1 are in clinical development for treatment of these inflammatory bowel diseases. Overall, integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target the ligand binding site, or the ligand itself.

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Section: New Leukocyte Integrin Antagonists For Ibdmentioning

confidence: 99%

Integrin-based therapeutics: biological basis, clinical use and new drugs

Ley

Rivera–Nieves

Sandborn

et al. 2016

Nat Rev Drug Discov

342

296

View full text Add to dashboard Cite

show abstract

“…Furthermore, long-term treatment is required for autoimmune diseases and potentially in breast cancer patients to with metastasis. Natalizumab needs to be administered intravenously over one hour every four weeks, whereas small molecule inhibitors of α4 integrin make oral bioavailability possible (52). Despite these advantages over Natalizumab, the application of small molecule inhibitors against α4 integrin target a biologically important interaction and therefore would need to be closely monitored for possible adverse reactions.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: VCAM-1 as a Potential Therapeutic Target in Metastasis

Chen

Massagué

2012

Clinical Cancer Research

126

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Interactions between disseminated tumor cells (DTCs) and stromal cells in the microenvironment are critical for tumor colonization of distal organs. Recent studies have shown that vascular cell adhesion molecule-1 (VCAM-1) is aberrantly expressed in breast cancer cells and mediates pro-metastatic tumor-stromal interactions. Moreover, the usefulness of VCAM-1 to DTCs in two different organs –lung and bone– is based on distinct mechanisms. In the lungs, VCAM-1 on the surface of cancer cells binds to its counter-receptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1 mediated activation of the PI3K growth and survival pathway in the cancer cells. In the bone marrow, cancer cell VCAM-1 attracts and tethers α4 integrin-expressing osteoclast progenitors to facilitate their maturation into multinucleated osteoclasts that mediate osteolytic metastasis. These findings highlight the importance of direct interactions between DTCs and stromal cells during tumor dissemination and draw attention to the possibility of targeting the α4 integrin-VCAM-1 interactions in metastatic breast cancer. Anti-α4 integrin inhibitors have been developed to treat various diseases driven by massive leukocyte infiltrates and have gained FDA approval or are undergoing clinical trials. Testing these drugs against tumor-stromal leukocyte interactions may provide a new strategy to suppress lung and bone relapse of breast cancer.

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“…AJM-300 is a novel small-molecule inhibitor of the a4 integrin subunit that was recently shown to prevent the development of experimental colitis induced by adoptive transfer of IL-10 À/À CD4 + T cells [166]. AJM-300 is currently in early clinical development for CD and has demonstrated good tolerability but no significant effect on clinical response compared with placebo.…”

Section: Cellular Adhesion Moleculesmentioning

confidence: 99%