Discovery of tetrahydrocarbazoles as dual pERK and pRb inhibitors.

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2017
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Abstract
The extracellular signal-regulated kinase (ERK) is one of the most important molecular targets for cancer that controls diverse cellular processes such as proliferation, survival, differentiation and motility. Similarly, the Rb (retinoblastoma protein) is a tumor suppressor protein and its function is to prevent excessive cell growth by inhibiting cell cycle progression. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. Herein, we discovered a new series of tetrahydrocarbazoles as dual inhibitors of pERK and pRb phosphorylation. The in-house small molecule library was screened for inhibition of pERK and pRb phosphorylation, which led to the discovery of tetrahydrocarbazole series of compounds as potential leads. N-(3-methylcyclopentyl)-6-nitro-2,3,4,4a,9,9a-hexahydro-1H-carbazol-2-amine (1) is the dual inhibitor lead identified through screening, displaying inhibition of pERK and pRb phosphorylation with IC values of 5.5 and 4.8 μM, respectively. A short structure-activity relationship (SAR) study has been performed, which identified another dual inhibitor 9-methyl-N-(4-methylbenzyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-2-amine (16) with IC values 4.4 and 3.5 μM for inhibition of pERK and pRb phosphorylation, respectively. This compound has a potential for further lead optimization to discover promising molecularly-targeted anticancer agents.
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kulkarni2017discovery Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Kulkarni, Mahesh R;Mane, Madhav S;Ghosh, Usha;Sharma, Rajiv;Lad, Nitin P;Srivastava, Ankita;Kulkarni-Almeida, Asha;Kharkar, Prashant S;Khedkar, Vijay M;Pandit, Shivaji S;
Journal European journal of medicinal chemistry
Year 2017
DOI
S0223-5234(17)30147-2
URL
Keywords Keywords not found

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