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Quinazoline Based HSP90 Inhibitors: Synthesis, Modeling Study and ADME Calculations Towards Breast Cancer Targeting
Hamed W El-Shafey1, Rania M Gomaa1, Shahenda M El-Messery1
1Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O.Box 35516 Mansoura, Egypt.
Abstract:
A new 2-thioquinazolinones series was designed and synthesized as HSP90 inhibitors based on the structure of hit compound VII obtained by virtual screening approach. Their in vitro anti-proliferative activity was evaluated against three human cancer cell lines rich in HSP90 namely; colorectal carcinoma (HCT-116), and cervical carcinoma (Hela), breast carcinoma (MCF-7). Compounds 5a, 5d, 5e and 9h showed a significant broad spectrum anti-proliferative activity against all tested cell lines. They were characterized by potent effect against breast cancer in particular with IC50 of 11.73, 8.56, 7.35 and 9.48 μM, respectively against Doxorubicin (IC50 4.17 μM). HSP90 ATPase activity inhibition assay were conducted where compound 5d exhibited the best IC50 with 1.58 μM compared to Tanespimycin (IC50 = 2.17 μM). Compounds 5a and 9h showed higher IC50 values of 3.21 and 3.41 μM, respectively. The effects of 5a, 5d and 9h on Her2 (a client proteins of HSP90) and HSP70 were evaluated in MCF-7 cells. All tested compounds were found to reduce Her2 protein expression levels and induce Hsp70 protein expression levels significantly, emphasizing that antibreast cancer effect is a consequence of HSP90 chaperone inhibition. Cell cycle analysis of MCF-7 cells treated with 5d showed cell cycle arrest at G2/M phase 38.89% and pro-apoptotic activity as indicated by annexin V-FITC staining by 22.42%. Molecular docking studies suggested mode of interaction to HSP90 via hydrogen bonding. ADME properties prediction of the active compounds suggested that they could be used as orally absorbed anticancer drug candidates.
Insights
New 2-thioquinazolinones were synthesized as HSP90 inhibitors, showing significant anti-cancer activity, particularly against breast cancer. These compounds effectively inhibit HSP90 ATPase activity and reduce client protein levels, indicating potential as orally absorbed anticancer drug candidates.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Heat shock protein 90 (HSP90) is a molecular chaperone overexpressed in various cancers.
- Inhibiting HSP90 disrupts the stability of client proteins crucial for cancer cell survival and proliferation.
- Virtual screening identified a hit compound (VII) as a starting point for designing novel HSP90 inhibitors.
Purpose of the Study:
- To design and synthesize a new series of 2-thioquinazolinones as HSP90 inhibitors.
- To evaluate the in vitro anti-proliferative activity of synthesized compounds against human cancer cell lines.
- To investigate the mechanism of action, including HSP90 ATPase inhibition and effects on client proteins.
Main Methods:
- Structure-based design and synthesis of 2-thioquinazolinones.
- In vitro anti-proliferative assays against HCT-116, Hela, and MCF-7 cancer cell lines.
- HSP90 ATPase activity inhibition assays and Western blot analysis for Her2 and HSP70.
- Cell cycle analysis and apoptosis assays (Annexin V-FITC staining).
- Molecular docking and ADME properties prediction.
Main Results:
- Compounds 5a, 5d, 5e, and 9h demonstrated significant broad-spectrum anti-proliferative activity.
- Potent activity against breast cancer (MCF-7) with IC50 values as low as 7.35 μM.
- Compound 5d showed potent HSP90 ATPase inhibition (IC50 = 1.58 μM), superior to Tanespimycin.
- Compounds reduced Her2 and increased HSP70 levels in MCF-7 cells, confirming HSP90 inhibition.
- Compound 5d induced G2/M cell cycle arrest and apoptosis.
- Molecular docking indicated interaction with HSP90 via hydrogen bonding.
Conclusions:
- The synthesized 2-thioquinazolinones are effective HSP90 inhibitors with significant anti-cancer properties.
- Compounds 5a, 5d, and 9h show promising activity against breast cancer through HSP90 inhibition.
- Predicted ADME properties suggest potential for oral bioavailability, positioning these compounds as candidates for anticancer drug development.
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