State-of-the-art of small molecule inhibitors of the TAM family: The point of view of the chemist

Baladi, Tom; Abet, Valentina; Piguel, Sandrine

doi:10.1016/j.ejmech.2015.10.003

Cited by 34 publications

(13 citation statements)

References 116 publications

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“…These results have encouraged a heated race in the development of novel and specific ways of inhibiting TAM signaling for use in cancer patients [24]. In fact, small-molecule kinase inhibitors, monoclonal antibodies, and soluble decoy TAM receptors are currently under development [25,26]. …”

Section: Introductionmentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

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The TAM receptor protein tyrosine kinases—Tyro3, Axl, and Mer—are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases. Importantly, TAM receptors have also been associated with cancer development and progression. In a cancer setting, TAM receptors have a dual regulatory role, controlling the initiation and progression of tumor development and, at the same time, the associated anti-tumor responses of diverse immune cells. Thus, modulation of TAM receptors has emerged as a potential novel strategy for cancer treatment. In this review, we discuss our current understanding of how TAM receptors control immunity, with a particular focus on the regulation of anti-tumor responses and its implications for cancer immunotherapy.

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Section: Introductionmentioning

confidence: 99%

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Paolino

Penninger

2016

Cancers

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“…While there are a number of small molecule inhibitors in preclinical and clinical development that have activity against TAM RTKs [6,93,94], many of these were not specifically designed as such and preferentially target other kinases. Here we review compounds rationally designed to target TAM RTKs (Table 1).…”

Section: Therapeutic Targeting Of Tam Receptorsmentioning

confidence: 99%

“…In biochemical assays, TP-0903 potently inhibits phosphorylation of AXL and its downstream target AKT with EC 50 (effective concentration) values of 222 and 350 nM, respectively [99]. However, it is also potent against TYRO3 and MERTK and the kinases Aurora A and B. Additionally, TP-0903 has a much lower IC 50 in cell viability assays indicating that functional effects may be mediated by off-target inhibition and not solely through AXL [93,99]. Despite this, evaluation of TP-0903 as an AXL inhibitor in solid tumors, AML, and CLL has moved forward [93].…”

Section: Therapeutic Targeting Of Tam Receptorsmentioning

confidence: 99%

“…ASP2215 has an IC 50 of 0.7 nM against AXL [93] and 0.29 nM against FLT3 [102] in enzymatic assays, potently inhibits phosphorylation of FLT3 in a FLT3-ITD + AML cell line, and prolongs survival in orthotopic xenograft models of FLT3-ITD + AML. Importantly, in a colony-forming assay treatment with ASP2215 was 100-fold more potent in the AML cell line compared to normal human granulocyte-macrophage precursors, suggesting a wide therapeutic window [102].…”

Section: Therapeutic Targeting Of Tam Receptorsmentioning

confidence: 99%

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Targeting the TAM Receptors in Leukemia

Huey

Minson

Earp

et al. 2016

Cancers

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Targeted inhibition of members of the TAM (TYRO-3, AXL, MERTK) family of receptor tyrosine kinases has recently been investigated as a novel strategy for treatment of hematologic malignancies. The physiologic functions of the TAM receptors in innate immune control, natural killer (NK) cell differentiation, efferocytosis, clearance of apoptotic debris, and hemostasis have previously been described and more recent data implicate TAM kinases as important regulators of erythropoiesis and megakaryopoiesis. The TAM receptors are aberrantly or ectopically expressed in many hematologic malignancies including acute myeloid leukemia, B- and T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. TAM receptors contribute to leukemic phenotypes through activation of pro-survival signaling pathways and interplay with other oncogenic proteins such as FLT3, LYN, and FGFR3. The TAM receptors also contribute to resistance to both cytotoxic chemotherapeutics and targeted agents, making them attractive therapeutic targets. A number of translational strategies for TAM inhibition are in development, including small molecule inhibitors, ligand traps, and monoclonal antibodies. Emerging areas of research include modulation of TAM receptors to enhance anti-tumor immunity, potential roles for TYRO-3 in leukemogenesis, and the function of the bone marrow microenvironment in mediating resistance to TAM inhibition.

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“…With this background, we explored introduction of macrocycles into MerTK inhibitors. 20 Indeed, compound 3 proved active against MerTK (IC 50 65 nM) with 20-and 30-fold selectivity over Axl (IC 50 1300 nM) and Tyro3 (IC 50 2000 nM), respectively, and similar activity against Flt3 (IC 50 160 nM) in our in-house microfluidic capillary electrophoresis (MCE) assay. 21−23 The X-ray structure of 3 complexed with the MerTK kinase domain was also resolved at a 2.55 Å resolution ( Figure 2).…”

mentioning

confidence: 92%

Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors

Wang

Liu

Zhang

et al. 2016

ACS Med. Chem. Lett.

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Mer tyrosine kinase (MerTK) is aberrantly elevated in various tumor cells and has a normal anti-inflammatory role in the innate immune system. Inhibition of MerTK may provide dual effects against these MerTK-expressing tumors through reducing cancer cell survival and redirecting the innate immune response. Recently, we have designed novel and potent macrocyclic pyrrolopyrimidines as MerTK inhibitors using a structure-based approach. The most active macrocycles had an EC 50 below 40 nM in a cell-based MerTK phosphor-protein ELISA assay. The X-ray structure of macrocyclic analogue 3 complexed with MerTK was also resolved and demonstrated macrocycles binding in the ATP binding pocket of the MerTK protein as anticipated. In addition, the lead compound 16 (UNC3133) had a 1.6 h half-life and 16% oral bioavailability in a mouse PK study.

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State-of-the-art of small molecule inhibitors of the TAM family: The point of view of the chemist

Cited by 34 publications

References 116 publications

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

The Role of TAM Family Receptors in Immune Cell Function: Implications for Cancer Therapy

Targeting the TAM Receptors in Leukemia

Design and Synthesis of Novel Macrocyclic Mer Tyrosine Kinase Inhibitors

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