Imidazo[2,1-b]thiazoles: Multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family of receptor tyrosine kinases

Fidanze, Steve; Erickson, Scott; Wang, Gary T.; Mantei, Robert A.; Clark, Richard F.; Sorensen, Bryan K.; Bamaung, Nwe Y.; Kovar, Peter; Johnson, Eric F.; Swinger, Kerren K.; Stewart, Kent D.; Zhang, Qian; Tucker, Lora; Pappano, William N.; Wilsbacher, Julie L.; Wang, Jieyi; Sheppard, George S.; Bell, Randy L.; Davidsen, Steven K.; Hubbard, Robert D.

doi:10.1016/j.bmcl.2010.03.015

Cited by 52 publications

(19 citation statements)

References 12 publications

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“…Abbott has reported another bicyclic system structures from a screen of Abbott's compound collection with an imidazo[2,1-b]thiazole scaffold, to act as multi-targeted inhibitors of both IGF-1R and members which belonged to the EGFR family [62]. After several rounds of optimization, compound 38 was picked out for Xray crystallography assay with EGFR, which had balanced activities against IGF-1R, EGFR and ErbB2, showing IC 50 values of 130 nM, 63 nM, 370 nM respectively.…”

Section: Imidazothiazolesmentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Xue¹,

Cao²,

Zhong³

et al. 2012

CPD

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The insulin-like growth factors (IGF) and their receptors play pivotal roles in cellular signaling transduction and thus regulate cell growth, differentiation, apoptosis, transformation and other important physiological progresses. The insulin-like growth factor 1 receptor (IGF-1R) mainly engages in the Ras/mitogen-activated protein kinase (MAPK) pathway and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, and also forms cross-talk with the epidermal growth factor receptor (EGFR) pathway. Currently, it draws more attention since its overexpression has been demonstrated in various human cancers, such as colorectal cancer, breast cancer, prostate cancer and lung tumors, thus the strategy targeting the IGF-1R would be promising in treatment of these cancers. There are already dozens of agents developed for the inhibition of IGF-1R, which are categorized into monoclonal antibodies, small molecule inhibitors and so on. While in this review, small molecule inhibitors would be the focus for detailed discussion. Herein, we updated previously reported research papers and reviews in this field and summarized developments of small molecule inhibitors up to 2011. Finally, we proposed the application of network pharmacology methods to reconsider the clinical use of inhibitors with concomitant IR inhibition or other kinases inhibition, hoping that more optimal combinations would be obtained for cancer therapy.

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Section: Imidazothiazolesmentioning

confidence: 99%

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Xue¹,

Cao²,

Zhong³

et al. 2012

CPD

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“…The choice of any one should be fine, though the selection of chain A was a little arbitrary. At the time of analysis 49 EGFR structures of kinase domain were obtained: 1M14, 1M17,[17] 1XKK,[18] 2EB2, 2EB3, 3UG1, 3UG2, 3VJN, 3VJO,[19] 2GS2, 2GS7,[20] 2ITN, 2ITO, 2ITP, 2ITQ, 2ITT, 2ITU, 2ITV, 2ITW, 2ITX, 2ITY, 2ITZ, 2J6M,[21] 2JIT, 2JIU,[9] 2RF9, 2RFD, 2RFE,[22] 2RGP,[23] 3BEL,[24] 3GT8,[25] 3LZB,[26] 3POZ,[27] 3W2O, 3W2R, 3W2S,[28] 3W32, 3W33,[29] 4HJO,[7] 4I1Z, 4I20, 4I21, 4I22, 4I23,[8] 4JQ7, 4JQ8, 4JR3, 4JRV,[30] 4LI5. [31]…”

Section: Methodsmentioning

confidence: 99%

Statistical analysis of EGFR structures’ performance in virtual screening

Dong

2015

J Comput Aided Mol Des

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In this work the ability of EGFR structures to distinguish true inhibitors from decoys in docking and MM-PBSA is assessed by statistical procedures. The docking performance depends critically on the receptor conformation and bound state. The enrichment of known inhibitors is well correlated with the difference between EGFR structures rather than the bound-ligand property. The optimal structures for virtual screening can be selected based purely on the complex information. And the mixed combination of distinct EGFR conformations is recommended for ensemble docking. In MM-PBSA, a variety of EGFR structures have identically good performance in the scoring and ranking of known inhibitors, indicating that the choice of the receptor structure has little effect on the screening.

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“…The reaction of 2-mercaptoimidazoles with N-(sulfonyl)phenyldichloroacetaldimines leads to the formation of N-(2-phenylimidazo [2,1-b] [1,3]thiazol-3-yl)arenesulfonamides or N-(2-phenyl [1,3]thiazolo [3,2-a]benzimidazol-3-yl)arenesulfonamides. The advantages of the method for the preparation of the imidazothiazole and thiazolobenzimidazole derivatives are available starting reagents, catalyst-free one-step procedure, and high selectivity.…”

Section: Discussionmentioning

confidence: 99%

“…1 The prospects for application of biologically active imidazothiazoles stem from their ability of inhibiting or activating the various enzymes and receptors. [2][3][4][5] Importantly, these compounds show antitumor, [6][7][8][9][10][11] antimicrobial, 12,13 antidiabetic, 14 diuretic, 15 antihelmintic, 16 and fungicidal 17 properties. Besides, imidazo [2,1-b]thiazoles and thiazolo [3,2-a]benzimidazoles are useful reagents in heterocyclic chemistry and can be transformed into benzimidazolone derivatives.…”

Section: Introductionmentioning

confidence: 99%

Regioselective reaction of imidazole-2-thiols with N-sulfonylphenyldichloroacetaldimines: en route to novel sulfonylamino-substituted imidazo[2,1-b]thiazoles and thiazolo[3,2-a]benzimidazoles

Serykh¹,

Kaliev²,

Ushakov³

et al. 2017

Arkivoc

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The reaction of N- (2,2-dichloro-2-phenylethylidene)arenesulfonamides with 2-mercaptoimidazoles affords N- -(2-phenyl[1,3]thiazolo [3,2-a]benzimidazol-3-yl)arenesulfonamides. Formation of the annulated heterocyclic derivatives is tentatively triggered by a nucleophilic addition of mercaptoimidazole to the activated azomethine group of halogen-containing imines followed by intramolecular heterocyclization and aromatization.

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Imidazo[2,1-b]thiazoles: Multitargeted inhibitors of both the insulin-like growth factor receptor and members of the epidermal growth factor family of receptor tyrosine kinases

Cited by 52 publications

References 12 publications

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Insulin-like Growth Factor-1 Receptor (IGF-1R) Kinase Inhibitors in Cancer Therapy: Advances and Perspectives

Statistical analysis of EGFR structures’ performance in virtual screening

Regioselective reaction of imidazole-2-thiols with N-sulfonylphenyldichloroacetaldimines: en route to novel sulfonylamino-substituted imidazo[2,1-b]thiazoles and thiazolo[3,2-a]benzimidazoles

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