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7,8-dichloro-1-oxo-尾-carbolines as a versatile scaffold for the development of potent and selective kinase inhibitors with unusual binding modes.

Chart 1
<div class='caption-title'>Reagents and conditionsforpart A: (i) NaH, DMF, 40 °C, 1 h, then CH3I, roomtemp, 5 h; (ii) POCl3, DMF, room temp, 40 min, then 60°C, 4 h; (iii) hydrazine, 1,4-dioxane, reflux, 3 h. Percentagesgiven correspond to relative yields.</div>
<div class='caption-title'>Reagents and conditionsforpart A: (i) cyclohexanone, NH3, NH4Cl, 100 °C,1 h, sealed tube; (ii) TEBAC, K2CO3, CH3CN, room temp, 15 min, then 22 and (CH3O)2SO2, room temp, 12 h. Percentages given correspond to relativeyields.</div>
Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F
OpenAccess logo J Med Chem 55 403-13 (2012)
Related entries: 3cxw, 3cy2

Cited: 33 times
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Abstract

Development of both potent and selective kinase inhibitors is a challenging task in modern drug discovery. The innate promiscuity of kinase inhibitors largely results from ATP-mimetic binding to the kinase hinge region. We present a novel class of substituted 7,8-dichloro-1-oxo-尾-carbolines based on the distinct structural features of the alkaloid bauerine C whose kinase inhibitory activity does not rely on canonical ATP-mimetic hinge interactions. Intriguingly, cocrystal structures revealed an unexpected inverted binding mode and the presence of halogen bonds with kinase backbone residues. The compounds exhibit excellent selectivity over a comprehensive panel of human protein kinases while inhibiting selected kinases such as the oncogenic PIM1 at low nanomolar concentrations. Together, our biochemical and structural data suggest that this scaffold may serve as a valuable template for the design and development of specific inhibitors of various kinases including the PIM family of kinases, CLKs, DAPK3 (ZIPK), BMP2K (BIKE), and others.

Reviews - 3bhy mentioned but not cited (1)

  1. Ulke-Lem茅e A, MacDonald JA. Pharmaceuticals (Basel) 3 1739-1760 (2010)

Articles - 3bhy mentioned but not cited (7)

  1. Huber K, Brault L, Fedorov O, Gasser C, Filippakopoulos P, Bullock AN, Fabbro D, Trappe J, Schwaller J, Knapp S, Bracher F. J Med Chem 55 403-413 (2012)
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Reviews citing this publication (2)

  1. Farag AK, Roh EJ. Med Res Rev 39 349-385 (2019)
  2. Ogawa N, Yuki H, Tanaka A. Expert Opin Drug Discov 7 1177-1192 (2012)

Articles citing this publication (23)

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  8. Lori C, Lantella A, Pasquo A, Alexander LT, Knapp S, Chiaraluce R, Consalvi V. PLoS One 8 e64824 (2013)
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  18. Str枚dke B, Gehring AP, Bracher F. Arch Pharm (Weinheim) 348 125-131 (2015)
  19. Ramakrishnan C, Mary Thangakani A, Velmurugan D, Anantha Krishnan D, Sekijima M, Akiyama Y, Gromiha MM. J Biomol Struct Dyn 36 1566-1576 (2018)
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