Effects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells

Koda, Yuki; Itoh, Mai; Tohda, Shuji

doi:10.21873/anticanres.12208

Cited by 5 publications

(6 citation statements)

References 13 publications

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“…NPS-1034 (Small molecule) Axl , MetAnti-cancer properties in EGFR inhibitor resistant lung cancer cell lines and xenograft models [165]. Spiroindoline-based analogs (Small molecule) Tyro3 None reported.UNC569 (Small molecule) MerTK, Axl, Tyro3 Anti-cancer properties in ALL and AML cell lines [146, 147]. UNC1062 (Small molecule) MerTK Anti-cancer properties AML cell lines [147].…”

Section: Main Textmentioning

confidence: 99%

“…Spiroindoline-based analogs (Small molecule) Tyro3 None reported.UNC569 (Small molecule) MerTK, Axl, Tyro3 Anti-cancer properties in ALL and AML cell lines [146, 147]. UNC1062 (Small molecule) MerTK Anti-cancer properties AML cell lines [147]. UNC1666 (Small molecule) MerTK , Flt3Reduces colony formation in AML cell lines [148].…”

Section: Main Textmentioning

confidence: 99%

“…UNC569 has also been utilized in vivo to study phagocytosis by retinal pigment epithelium cells [151]. UNC1062, as well as UNC569, induces apoptosis and decreases cell growth in AML cell lines [147]. UNC1666 is a dual MerTK and FLT3 inhibitor that reduces colony formation in MerTK- or FLT3-ITD- expressing AML cell lines [148].…”

Section: Main Textmentioning

confidence: 99%

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Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Myers¹,

Amend²,

2019

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Tumor-associated macrophages are an abundant cell type in the tumor microenvironment. These macrophages serve as a promising target for treatment of cancer due to their roles in promoting cancer progression and simultaneous immunosuppression. The TAM receptors (Tyro3, Axl and MerTK) are promising therapeutic targets on tumor-associated macrophages. The TAM receptors are a family of receptor tyrosine kinases with shared ligands Gas6 and Protein S that skew macrophage polarization towards a pro-tumor M2-like phenotype. In macrophages, the TAM receptors also promote apoptotic cell clearance, a tumor-promoting process called efferocytosis. The TAM receptors bind the “eat-me” signal phosphatidylserine on apoptotic cell membranes using Gas6 and Protein S as bridging ligands. Post-efferocytosis, macrophages are further polarized to a pro-tumor M2-like phenotype and secrete increased levels of immunosuppressive cytokines. Since M2 polarization and efferocytosis are tumor-promoting processes, the TAM receptors on macrophages serve as exciting targets for cancer therapy. Current TAM receptor-directed therapies in preclinical development and clinical trials may have anti-cancer effects though impacting macrophage phenotype and function in addition to the cancer cells.

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Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Myers¹,

Amend²,

2019

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“…1 H NMR (500 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 10.09 (s, 1H), 9.36 (s, 1H), 8.28 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.66 (dd, J = 9.0, 5.1 Hz, 2H), 7.35 (d, J = 4.4 Hz, 2H), 7.20-7.12 (m, 4H), 6.75 (d, J = 8.3 Hz, 2H), 6.35 (d, J = 5.6 Hz, 1H), 3.55 (t, J = 4.7 Hz, 2H), 3.51 (t, J = 4.5 Hz, 2H), 3.01 (t, J = 4.6 Hz, 2H), 2.94 (t, J = 4.7 Hz, 2H), 2.01 (s, 3H), 1.51 (d, J = 8.5 Hz, 4H). 13 7.72 (d, J = 8.9 Hz, 2H), 7.69-7.59 (m, 6H), 7.21 (d, J = 8.9 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 6.48 (d, J = 5.6 Hz, 1H), 3.56 (t, J = 4.4 Hz, 4H), 3.25 (q, J = 6.7 Hz, 2H), 2.38-2.27 (m, 6H), 1.66 (t, J = 7.05 Hz, 2H), 1.51 (d, J = 10.35 Hz, 4H). 13 Compound 18e: White solid, yield: 10.9%.…”

Section: General Procedures For Preparation Of the Title Compounds 18...mentioning

confidence: 99%

“…Mer inhibitors are broadly classified into two types: aminopyrimidine pyrazole (pyrrole) and aminopyrimidine series ( Figure 1 ). The initial small-molecule Mer inhibitor UNC569 effectively inhibits Mer and downstream signaling pathways ERK and AKT but suffers from poor pharmacokinetic properties [ 6 , 7 ]. Subsequent developments, such as compounds UNC2225 and MRX-2843 derived from UNC569 [ 8 , 9 , 10 , 11 ], exhibit enhanced inhibition of Mer signal transduction, improved pharmacokinetic properties, and favorable drug-like characteristics.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors

Huang,

Chen,

Yang

et al. 2024

Molecules

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Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

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Macrophage‐Mediated Tumor Cell Phagocytosis: Opportunity for Nanomedicine Intervention

Zhou

Liu

Huang

2020

Adv Funct Materials

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Macrophages are one of the most abundant non‐malignant cells in the tumor microenvironment, playing critical roles in mediating tumor immunity. As important innate immune cells, macrophages possess the potential to engulf tumor cells and present tumor‐specific antigens for adaptive antitumor immunity induction, leading to growing interest in targeting macrophage phagocytosis for cancer immunotherapy. Nevertheless, live tumor cells have evolved to evade phagocytosis by macrophages via the extensive expression of anti‐phagocytic molecules, such as CD47. In addition, macrophages also rapidly recognize and engulf apoptotic cells (efferocytosis) in the tumor microenvironment, which inhibits inflammatory responses and facilitates immune escape of tumor cells. Thus, intervention of macrophage phagocytosis by blocking anti‐phagocytic signals on live tumor cells or inhibiting tumor efferocytosis presents a promising strategy for the development of cancer immunotherapies. Here, the regulation of macrophage‐mediated tumor cell phagocytosis is first summarized, followed by an overview of strategies targeting macrophage phagocytosis for the development of antitumor therapies. Given the potential off‐target effects associated with the administration of traditional therapeutics (for example, monoclonal antibodies and small molecule inhibitors), the opportunity for nanomedicine in macrophage phagocytosis intervention is highlighted.

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Effects of MERTK Inhibitors UNC569 and UNC1062 on the Growth of Acute Myeloid Leukaemia Cells

Abstract: These MERTK inhibitors are potential molecular-targeted drugs for treating AML expressing constitutively phosphorylated MERTK.

Cited by 5 publications

References 13 publications

Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors

Macrophage‐Mediated Tumor Cell Phagocytosis: Opportunity for Nanomedicine Intervention

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