Optimization of a novel kinase inhibitor scaffold for the dual inhibition of JAK2 and FAK kinases

Zificsak, Craig A.; Gingrich, Diane E.; Breslin, Henry J.; Dunn, Derek; Milkiewicz, Karen L.; Theroff, Jay; Thieu, Tho V.; Underiner, Ted L.; Weinberg, Linda R.; Aimone, Lisa D.; Albom, Mark S.; Mason, J. L.; Saville, Lisa; Husten, Jean; Angeles, Thelma S.; Finn, James P.; Jan, Mahfuza; O'Kane, Teresa M.; Dobrzański, Paweł; Dorsey, Bruce D.

doi:10.1016/j.bmcl.2011.11.049

Cited by 17 publications

(7 citation statements)

References 12 publications

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“…Based on a previously identified ALK inhibitor and a JAK2 (janus kinase 2) inhibitor, scientists in Cephalon Inc. developed a class of JAK2/FAK dual inhibitors with a pyrrolo[2,1- f ][1,2,4]triazine scaffold; the representative compound 20 (Figure ) can effectively inhibit the enzymatic activity of JAK2 (IC 50 = 2.5 nM) and FAK (IC 50 = 5 nM) . Compound 20 has a desirable pharmacokinetic profile and is orally bioavailable.…”

Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

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Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Sun

2020

J. Med. Chem.

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Focal adhesion kinase (FAK) is a nonreceptor intracellular tyrosine kinase that plays an essential role in cancer cell adhesion, survival, proliferation, and migration through both its enzymatic activities and scaffolding functions. Overexpression of FAK has been found in many human cancer cells from different origins, which promotes tumor progression and influences clinical outcomes in different classes of human tumors. Therefore, FAK has been considered as a promising target for small molecule anticancer drug development. Many FAK inhibitors targeting different domains of FAK with various mechanisms of functions have been reported, including kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors. In addition, FAK-targeting PROTACs, which can induce the degradation of FAK, have also been developed. In this Perspective, we summarized the progress in the development of small molecular FAK inhibitors and proposed the perspectives for the future development of agents targeting FAK.

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Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

“…116 The most potent compound 5) can effectively inhibit the enzymatic activity of JAK2 (IC 50 = 2.5 nM) and FAK (IC 50 = 5 nM). 117 Compound 20 has a desirable pharmacokinetic profile and is orally bioavailable. It can strongly inhibit pStat3 and reduce the level of FAK phosphorylation in vitro.…”

Section: The Development Of Fak Inhibitorsmentioning

confidence: 99%

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Sun

2020

J. Med. Chem.

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“…Cephalon also reported a designed dual-target inhibitor from the highly potent C7-aryl substituted 21, based on the same core as 20 [35]. While most C7 aryl substituents were potent JAK2 inhibitors, many were poor FAK inhibitors with poor cellular activity.…”

Section: Key Termmentioning

confidence: 94%

Selective JAK Inhibitors

et al. 2014

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Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.

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“…Pyrrolopyrimidines from Abbott [69] have the 5-membered ring replace the C-5-Cl and C-6-H (pyrimidine numbering) of DAPs, adding another potential H-bond donor (the pyrrole NH) to the core to form a D-A-D registry for putative 2,7-Substituted pyrrolotriazines discovered at Cephalon/ Teva [70] constitute an inventive variation on a previously known heteroaromatic system. Pyrrolo[2,1-f][1,2,4]triazine inhibitors of ALK [71], JAK2 or FAK [72,73] are exemplified. Here, the pyrrole ring replaces the C-5-Cl and C-4-NH of DAPs, serving as a platform for the C-7 substituent (38 in Figure 8 for numbering), while the pyrrole nitrogen becomes a bridgehead atom, rendering the 6-member ring a triazine instead of pyrimidine.…”

Section: Constrained 56-bicyclic Heteroaromatic Analogs Of Dapsmentioning

confidence: 99%

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

Mesaros

Ott

Dorsey

2014

Expert Opinion on Therapeutic Patents

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Optimization of a novel kinase inhibitor scaffold for the dual inhibition of JAK2 and FAK kinases

Cited by 17 publications

References 12 publications

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)

Selective JAK Inhibitors

Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review

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