Discovery of tetrahydrocarbazoles as dual pERK and pRb inhibitors
Mahesh R Kulkarni1, Madhav S Mane2, Usha Ghosh2
1Post Graduate and Research Centre, Department of Chemistry, Padmashri Vikhe Patil College of Arts, Science and Commerce, Pravaranagar, A/P Loni, Tal. Rahata, Dist. Ahmednagar 413713, India; Department of Medicinal Chemistry, Piramal Enterprises Limited 1, Nirlon Complex, Off Western Exp. Highway, Near NSE Complex, Goregaon East, Mumbai, Maharashtra 400 063, India.
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 IC50 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 IC50 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.
Insights
Researchers discovered novel tetrahydrocarbazole compounds that simultaneously inhibit phosphorylated extracellular signal-regulated kinase (pERK) and phosphorylated retinoblastoma protein (pRb). These dual inhibitors show promise for developing targeted anticancer therapies.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Extracellular signal-regulated kinase (ERK) and retinoblastoma protein (Rb) are crucial regulators of cell proliferation and survival, making them key targets in cancer therapy.
- Dysregulation of ERK and Rb pathways contributes to uncontrolled cell growth and tumor development.
Purpose of the Study:
- To identify novel small molecules capable of simultaneously inhibiting both phosphorylated ERK (pERK) and phosphorylated Rb (pRb).
- To explore the potential of tetrahydrocarbazole derivatives as dual inhibitors for targeted cancer treatment.
Main Methods:
- Screening of an in-house small molecule library for compounds inhibiting pERK and pRb phosphorylation.
- Structure-activity relationship (SAR) studies to optimize lead compounds.
- Determination of IC50 values for dual inhibition of pERK and pRb phosphorylation.
Main Results:
- Discovery of a tetrahydrocarbazole series as potent dual inhibitors of pERK and pRb phosphorylation.
- Identification of compound 1 (N-(3-methylcyclopentyl)-6-nitro-2,3,4,4a,9,9a-hexahydro-1H-carbazol-2-amine) with IC50 values of 5.5 μM (pERK) and 4.8 μM (pRb).
- Identification of compound 16 (9-methyl-N-(4-methylbenzyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-2-amine) with improved IC50 values of 4.4 μM (pERK) and 3.5 μM (pRb).
Conclusions:
- Tetrahydrocarbazole derivatives represent a promising scaffold for developing dual inhibitors targeting pERK and pRb.
- Compound 16 demonstrates significant potential for further optimization into novel molecularly-targeted anticancer agents.
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