New aminopyrimidine derivatives as inhibitors of the TAM family

Traoré, Ténin; Cavagnino, Andrea; Saettel, Nicolas; Radvanyi, François; Piguel, Sandrine; Bernard‐Pierrot, Isabelle; Stoven, Véronique; Legraverend, Michel

doi:10.1016/j.ejmech.2013.10.037

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…Importantly, experimental evidence demonstrates that TAM antagonism can efficiently revert these processes [22,126,127,128,129,130], underscoring the potential benefits of TAM inhibition for cancer therapy (Figure 3). Together, these consistent results have encouraged the development of novel and specific ways of inhibiting TAM signaling in tumor cells for clinical use [24,131,132]. In fact, the first clinical trial with an anti-Axl specific small molecule inhibitor for treatment of acute myeloid leukemia and non-small cell lung cancer is currently underway [133], and several others newly synthetized inhibitors specific for TAM receptors are being tested at a preclinical stage [134,135].…”

Section: Taming Anti-tumor Immunitymentioning

confidence: 97%

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: Taming Anti-tumor Immunitymentioning

confidence: 97%

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

Paolino

Penninger

2016

Cancers

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“…The synthesis of inhibitors more selective for the TAM family has been recently reported. In particular, the type II BMS777607 was modified by replacing its pyridine with a purine [94] or with an aminopyrimidine [106] ring obtaining compounds with enhanced selectivity. In both cases, ring modification increased the selectivity towards TAM allowing the synthesis of likely type II inhibitors.…”

Section: Development Of Axl Inhibitors 41 From Chemistry To Pharmacmentioning

confidence: 99%

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Corno

Gatti

Lanzi

et al. 2016

CMC

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Aberrant expression and activation of receptor tyrosine kinases (RTK) is a frequent feature of tumor cells that may underlie tumor aggressiveness. Among RTK, Axl, a member of the Tyro3-Axl-Mer family, represents a potential therapeutic target in different tumor types given its over-expression which leads to activation of oncogenic signaling promoting cell proliferation and survival, as well as migration and invasion. Axl can promote aggressiveness of various cell types through PI3K/Akt and/or MAPK/ERK, and its expression can be transcriptionally regulated by multiple factors. Deregulated Axl expression and activation have been shown to be implicated in reduced sensitivity of tumor cells to target-specific and conventional antitumor agents, but the precise mechanism underlying these phenomena are still poorly understood. Several small molecules acting as Axl inhibitors have been reported, and some of them are undergoing clinical investigation. In this review, we describe Axl biological functions, its expression in cancer and in drug-resistant tumor cells and the development of inhibitors tailored to this receptor tyrosine kinase.

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“…The current study shows that Tyro3, Axl, and Mertk are differentially expressed on several cell subtypes that contribute to the tumor microenvironment, whereby Axl is preferentially expressed on E0771 tumor cells, while macrophages, including peritoneal macrophages, bone marrow-derived macrophages, and tumorassociated macrophages have higher Mertk/Axl ratios. Subsequently, we used a combination strategy with a pan-TAM inhibitor, BMS-777607 (41)(42)(43), and anti-PD-1 mAb to test the therapeutic potential in a preclinical model of triplenegative breast cancer. Our data demonstrated that combining of TAM kinase inhibitor and anti-PD-1 antibody significantly inhibited tumor growth compared with either single therapy regimen alone or control (vehicle drug) and decreased incidence of lung metastasis.…”

Section: Introductionmentioning

confidence: 99%

Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer

et al. 2019

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Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS!TAM receptor!PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti-PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti-PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti-PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy. Significance: These findings show that pan-inhibition of TAM receptors in combination with anti-PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.

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New aminopyrimidine derivatives as inhibitors of the TAM family

Cited by 12 publications

References 24 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

Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells

Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer

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