<b>UNC2025</b>, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

Zhang, Weihe; DeRyckere, Deborah; Hunter, Debra; Liu, Jing; Stashko, Michael A.; Minson, Katherine A.; Cummings, Christopher T.; Lee, Minjung; Glaros, Trevor; Newton, Dianne L.; Sather, Susan; Zou, Dehui; Kireev, Dmitri; Janzen, William P.; Earp, H. Shelton; Graham, Douglas K.; Frye, Stephen V.; Wang, Xiaodong

doi:10.1021/jm500749d

Cited by 133 publications

(166 citation statements)

References 54 publications

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“…Specific MerTK antagonists (UNC1062 and UNC2025; Meryx Pharma) significantly reduced myelin uptake in both microglia and MDMs, with the effect being most evident in the TGF-b-treated cells, likely due to the enhanced MerTK expression in these cells (25,34). MerTK mRNA expression levels were further increased in TGF-b-treated cells following myelin ingestion, potentially contributing to enhanced phagocytic activity.…”

Section: Discussionmentioning

confidence: 99%

“…7B). UNC1062 (MerTK IC50 = 1.1 nmol) is a first-generation MerTK antagonist; UNC2025 (MerTK IC50 = 0.74 nmol) is a secondgeneration antagonist with improved drug metabolism and pharmacokinetic properties (25,26). A 1-h pretreatment with both MerTK antagonists (1 mmol) significantly decreased phagocytosis of human myelin in M0, Mtgf, and M2c MDMs (Fig.…”

Section: Phagocytosis Correlates With Mertk Expression and Can Be Inhmentioning

confidence: 94%

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MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

Healy

Perron

Won

et al. 2016

The Journal of Immunology

141

160

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Multifocal inflammatory lesions featuring destruction of lipid-rich myelin are pathologic hallmarks of multiple sclerosis. Lesion activity is assessed by the extent and composition of myelin uptake by myeloid cells present in such lesions. In the inflamed CNS, myeloid cells are comprised of brain-resident microglia, an endogenous cell population, and monocyte-derived macrophages, which infiltrate from the systemic compartment. Using microglia isolated from the adult human brain, we demonstrate that myelin phagocytosis is dependent on the polarization state of the cells. Myelin ingestion is significantly enhanced in cells exposed to TGF-β compared with resting basal conditions and markedly reduced in classically activated polarized cells. Transcriptional analysis indicated that TGF-β–treated microglia closely resembled M0 cells. The tyrosine kinase phagocytic receptor MerTK was one of the most upregulated among a select number of differentially expressed genes in TGF-β–treated microglia. In contrast, MerTK and its known ligands, growth arrest-specific 6 and Protein S, were downregulated in classically activated cells. MerTK expression and myelin phagocytosis were higher in CNS-derived microglia than observed in monocyte-derived macrophages, both basally and under all tested polarization conditions. Specific MerTK inhibitors reduced myelin phagocytosis and the resultant anti-inflammatory biased cytokine responses for both cell types. Defining and modulating the mechanisms that regulate myelin phagocytosis has the potential to impact lesion and disease evolution in multiple sclerosis. Relevant effects would include enhancing myelin clearance, increasing anti-inflammatory molecule production by myeloid cells, and thereby permitting subsequent tissue repair.

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Section: Discussionmentioning

confidence: 99%

Section: Phagocytosis Correlates With Mertk Expression and Can Be Inhmentioning

confidence: 94%

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

Healy

Perron

Won

et al. 2016

The Journal of Immunology

141

160

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“…Here, we describe an SBVS protocol that has been used to identify inhibitors of Mer kinase, a promising therapeutic target against acute lymphoblastic leukemia (ALL) [10,14]. Prior to the start of this campaign, we had already identified a lead series of potent Mer inhibitors [15][16][17][18] and the objective of this VS campaign was to identify backup leads whose structures would significantly differ from the lead compound, UNC2025 [19]. This SBVS project features all critical screening and confirmation steps, including docking, scoring, post-scoring, triage, procurement, and experimental testing.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Virtual Screening of Commercially Available Compound Libraries

Kireev

2016

Methods in Molecular Biology

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Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

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“…Overall, the currently available data support a hypothesis that Mer kinase inhibitors might be developed into selective therapeutics for ALL. We have previously reported several series of potent Mer inhibitors, including compound 2 (see Figure 1) [4], resulting from structure-based design[4-9]. While our Mer project is progressing through IND enabling studies with an initial clinical candidate from this series, we are also working on identifying a chemically dissimilar back-up series that might circumvent potential flaws inherent to the current lead series.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Mer kinase inhibitors by virtual screening using Structural Protein–Ligand Interaction Fingerprints

Stashko

Jayakody

et al. 2015

Bioorganic & Medicinal Chemistry

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Mer is a receptor tyrosine kinase implicated in acute lymphoblastic leukemia (ALL), the most common malignancy in children. The currently available data provide a rationale for development of Mer kinase inhibitors as cancer therapeutics that can target both cell autologous and immune-modulatory anti-tumor effects. We have previously reported several series of potent Mer inhibitors and the objective of the current report is to identify a chemically dissimilar back-up series that might circumvent potential, but currently unknown, flaws inherent to the lead series. To this end, we virtually screened a database of ∼3.8 million commercially available compounds using high-throughput docking followed by a filter involving Structural Protein-Ligand Interaction Fingerprints (SPLIF). SPLIF permits a quantitative assessment of whether a docking pose interacts with the protein target similarly to an endogenous or known synthetic ligand, and therefore helps to improve both sensitivity and specificity with respect to the docking score alone. Of the total of 62 experimentally tested compounds, 15 demonstrated reliable dose-dependent responses in the Mer in vitro kinase activity assay with inhibitory potencies ranging from 0.46 μM to 9.9 μM.

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UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor

Cited by 133 publications

References 54 publications

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

Structure-Based Virtual Screening of Commercially Available Compound Libraries

Discovery of Mer kinase inhibitors by virtual screening using Structural Protein–Ligand Interaction Fingerprints

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