Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase

Powell, Noel A.; Hoffman, Jennifer K.; Ciske, Fred L.; Kohrt, Jeffrey T.; Baxi, Sangita M.; Peng, Yun-Wen; Zhong, Min; Catana, Cornel; Ohren, Jeffrey F.; Perrin, Lisa A.; Edmunds, Jeremy J.

doi:10.1016/j.bmcl.2012.12.028

Cited by 14 publications

(8 citation statements)

References 7 publications

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“…Thus, development of agents that target TYRO3 with greater selectivity, particularly relative to the other TAM kinases, is desirable. High-throughput screening identified spiroindoline-2-carboxyindoles and 2,4-diaminopyrimidine-5-carboxamides as the first TYRO3-selective tyrosine kinase inhibitors [146,147,148]. Subsequent structure-activity relationship (SAR) studies on the 2,4-diaminopyrimidine-5-carboxamide backbone led to development of compounds with enhanced selectivity [146,147].…”

Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

“…High-throughput screening identified spiroindoline-2-carboxyindoles and 2,4-diaminopyrimidine-5-carboxamides as the first TYRO3-selective tyrosine kinase inhibitors [146,147,148]. Subsequent structure-activity relationship (SAR) studies on the 2,4-diaminopyrimidine-5-carboxamide backbone led to development of compounds with enhanced selectivity [146,147]. Of these, Compound 32 had greater than 100-fold selectivity for TYRO3 in a panel of 31 tyrosine kinases, including AXL, but was not as selective against MERTK (<10-fold).…”

Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

“…In addition, Compound 32 was not very potent (IC 50 = 70 nM) and had poor metabolic stability in liver microsome assays. Further SAR optimization led to discovery of derivative compounds with better activity and selectivity, reduced clearance in microsome assays, and improved solubility, including Compound 21, which is the most potent TYRO3 kinase inhibitor described to date (IC 50 = 0.7 nM), and Compound 19, which has greater than 100-fold selectivity for TYRO3 (IC 50 = 10 nM) over both MERTK and AXL [146,147]. However, these compounds have poor membrane permeability and oral bioavailability.…”

Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

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The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

Smart

Vasileiadi

Wang

et al. 2018

Cancers

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The TAM family (TYRO3, AXL, MERTK) tyrosine kinases play roles in diverse biological processes including immune regulation, clearance of apoptotic cells, platelet aggregation, and cell proliferation, survival, and migration. While AXL and MERTK have been extensively studied, less is known about TYRO3. Recent studies revealed roles for TYRO3 in cancer and suggest TYRO3 as a therapeutic target in this context. TYRO3 is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients with colorectal, hepatocellular, and breast cancers. Here we review the physiological roles for TYRO3 and its expression and functions in cancer cells and the tumor microenvironment, with emphasis on the signaling pathways that are regulated downstream of TYRO3 and emerging roles for TYRO3 in the immune system. Translational agents that target TYRO3 are also described.

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Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

Section: Tyro3 As a Therapeutic Targetmentioning

confidence: 99%

See 1 more Smart Citation

The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

Smart

Vasileiadi

Wang

et al. 2018

Cancers

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“…High-throughput screening identified a novel series of spiroindoline-based inhibitors as the first TYRO3-selective tyrosine kinase inhibitors. 156,182 Among these, compounds 21 and 24, 2,4-diaminopyrimidine-5-carboxamide inhibitors, are potent inhibitors of TYRO3 kinase (Sky IC 50 =0.0007 µM and 0.015 µM, respectively). 156 The compound 21, which replaces the entire amide sidechain with a 3-methylisoxazole from an 2, 4-diaminopyrimidine-5-carboxamide inhibitor, exhibited excellent selectivity in 46/48 kinases with some activity in MAP4K4 and Mer.…”

Section: Compounds 21 and 24mentioning

confidence: 99%

TYRO3: A potential therapeutic target in cancer

Hsu

Jou

Tsai

2019

Exp Biol Med (Maywood)

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TYRO3 belongs to the TAM (TYRO3, AXL, and MER) receptor family, a unique subfamily of the receptor tyrosine kinases. Members of TAM family share the same ligand, growth arrest-specific 6, and protein S. Although the signal transduction pathways of TYRO3 have not been evaluated in detail, overexpression and activation of TYRO3 receptor tyrosine kinase have been reported to promote cell proliferation, survival, tumorigenesis, migration, invasion, epithelial-mesenchymal transition, or chemoresistance in several human cancers. Targeting TYRO3 could break the kinase signaling, stimulate antitumor immunity, reduce tumor cell survival, and regain drug sensitivity. To date, there is no specific TYRO3-targeted drug, the effectiveness of targeting TYRO3 in cancer is worthy of further investigations. In this review, we present an update on molecular biology of TYRO3, summarize the development of potential inhibitors of TAM family members, and provide new insights in TYRO3-targeted treatment. Impact statement Cancer is among the leading causes of death worldwide. In 2016, 8.9 million people are estimated to have died from various forms of cancer. The current treatments, including surgery with chemotherapy and/or radiation therapy, are not effective enough to provide full protection from cancer, which highlights the need for developing novel therapy strategies. In this review, we summarize the molecular biology of a unique member of a subfamily of receptor tyrosine kinase, TYRO3 and discuss the new insights in TYRO3-targeted treatment for cancer therapy.

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“…A number of SAR studies describing optimization of selective inhibitors have been published [112,113,114] but there have been no further reports on preclinical development of the lead compounds.…”

Section: Therapeutic Targeting Of Tam Receptorsmentioning

confidence: 99%

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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Optimization of highly selective 2,4-diaminopyrimidine-5-carboxamide inhibitors of Sky kinase

Cited by 14 publications

References 7 publications

The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

TYRO3: A potential therapeutic target in cancer

Targeting the TAM Receptors in Leukemia

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