Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold

Homeodomain-interacting protein kinase 2 (HIPK2) is a Ser/Thr kinase controlling cell proliferation and survival, whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. SB203580, a p38 MAP kinase inhibitor, has been used as a tool to inhibit HIPK2 in cells, but here we show that its efficacy as HIPK2 inhibitor is negligible (IC50>40 µM). In contrast by altering the scaffold of the promiscuous CK2 inhibitor TBI a new class of HIPK2 inhibitors has been generated. One of these, TBID, displays toward HIPK2 unprecedented efficacy (IC50 = 0.33 µM) and selectivity (Gini coefficient 0.592 out of a panel of 76 kinases). The two other members of the HIPK family, HIPK1 and HIPK3, are also inhibited by TBID albeit less efficiently than HIPK2. The mode of action of TBID is competitive with respect to ATP, consistent with modelling. We also provide evidence that TBID is cell permeable by showing that HIPK2 activity is reduced in cells treated with TBID, although with an IC50 two orders of magnitude higher (about 50 µM) than in vitro.

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“…Instruments were used and procedures for compound characterization were carried out as published before [21], [22].…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Properties of a Selective Inhibitor of Homeodomain–Interacting Protein Kinase 2 (HIPK2)

et al. 2014

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“…2004; Akeno-Stuart et al 2007; Brandt et al 2010; Konings et al 2010; Samadi et al. 2012; Frett et al 2014; Sun et al 2014; Schwartz et al 2015; Dunna et al.…”

Section: Novel Investigational Tkis With Activity Against Retmentioning

confidence: 99%

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

Falco

Carlomagno

et al. 2017

Best Practice & Research Clinical Endocrinology & Metab

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RET receptor tyrosine kinase (RTK) acts as an ontogenetic driver in several human malignancies, including papillary and medullary thyroid carcinoma, lung adenocarcinoma, colorectal carcinoma, Spitzoid neoplasms, salivary gland carcinoma and chronic myeloproliferative disorders, secondary to as diverse genetic lesions as point-mutations, small insertions/deletions, and gene fusions. In other neoplasms, including breast and pancreatic adenocarcinoma, RET over-expression is up-regulated. Thus, small molecule compounds with RET tyrosine kinase inhibitory activity (TKIs) are being investigated for the targeted treatment of these malignancies. Multi-targeted TKIs with the RET inhibitory enzymatic activity of IC50 in the nanomolar range have entered clinical practice, registered for the treatment of medullary thyroid cancer (vandetanib, cabozantinib), radioiodine refractory non medullary thyroid cancer (lenvatinib, sorafenib) or cancers of other sites (sunitinib, ponatinib, regorafenib). This review summarizes mechanisms of RET oncogenic activity and properties of new TKIs that, at the preclinical stage, have demonstrated promising anti-RET activity.

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“…Both compounds were also found to be potent RET inhibitors [241,243,244]. Starting from a novel scaffold, it was shown recently that two compounds, 7c and 13g, displayed nanomolar/low micromolar selective activity against RET and were capable of inhibit the growth of RET-dependent cancer cells [245]. Starting from a novel scaffold, it was shown recently that two compounds, 7c and 13g, displayed nanomolar/low micromolar selective activity against RET and were capable of inhibit the growth of RET-dependent cancer cells [245].…”

Section: Terminatedmentioning

confidence: 99%

Inhibition of RET Activated Pathways: Novel Strategies for Therapeutic Intervention in Human Cancers

Santarpia¹,

Bottai²

2013

Current Pharmaceutical Design

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The REarranged during Transfection (RET) proto-oncogene and its activated signalling pathways have been shown to play an important role in cancer. RET genetic alterations including germline, somatic mutations and gene rearrangements have been demonstrated in several solid tumours, and numerous clinical trials using multikinase inhibitors containing RET as a target have shown significant activity against RET. Sorafenib and sunitinib have been approved for the treatment of renal, hepatocellular, gastrointestinal and pancreatic neuoendocrine carcinomas. Vandetanib has recently been approved for the treatment of unresectable locally advanced or metastatic medullary thyroid carcinomas. Novel genomic rearrangements and RET signalling interactions are now being studied in a variety of tumours and will provide the basis for new therapeutic strategies. Combination or sequential targeted therapies that are based on solid preclinical data regarding the inhibition of RET-mediated parallel or different -signalling pathways will likely be more effective.

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Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-thienyl)nicotinonitrile scaffold

Cited by 47 publications

References 27 publications

Synthesis and Properties of a Selective Inhibitor of Homeodomain–Interacting Protein Kinase 2 (HIPK2)

Synthesis and Properties of a Selective Inhibitor of Homeodomain–Interacting Protein Kinase 2 (HIPK2)

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

Inhibition of RET Activated Pathways: Novel Strategies for Therapeutic Intervention in Human Cancers

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