Exploring target selectivity in designing and identifying PI3Kα inhibitors for triple negative breast cancer with
Debojyoti Halder1, Shreya Mukherjee2, R S Jeyaprakash3
1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India. debojyotihaldar955@gmail.com.
Abstract:
Triple-negative breast cancer (TNBC) is one of the most fatal malignancies in the world, accounting for 42% of all deaths due to metastasis. The significant development is hindered by the multi-drug resistance and poor patient compliance. PIK3CA gene mutation is one of the important causes of TNBC, which causes dysregulation of the cell cycle and cell proliferation. PI3Kα selective inhibition can decrease the TNBC by a significant level with minimal off-target effects. Novel compounds with high selectivity towards PI3Kα are crucial for treating TNBC. After extensive literature analysis, it was observed that fragment-based drug discovery, combined with structure-based virtual screening and bioisosteric replacement strategy, could provide a novel way for hit-to-lead optimization. The present study focussed on the fragment-based direct linking of 11269 moieties of the ChemDiv fragment library, - to generate novel moieties and further screened them using molecular docking, MMGBSA, and target selectivity analysis. Further, the top 2 moieties - Djh1 and Djh2 were selected after MMGBSA analysis and target selectivity prediction towards kinase. Further induced fit docking (IFD) analysis, DFT analysis, and MD simulation were employed to establish that - Djh1 and Djh2 could act as potential hit molecules for selective inhibition of PI3Kα. Further bioisosteric replacement, docking analysis, and target selectivity analysis were performed with the bioisosteres. The top two bioisosteres of Djh1 - Compound 10, Compound 06 represented excellent efficacy and selectivity towards PI3Kα in the treatment of TNBC after analysis of ADMET analysis. Further, in vitro and in vivo analysis might prove the effectiveness of the hit compounds.
Insights
Researchers developed novel compounds targeting PI3Kα to treat triple-negative breast cancer (TNBC). This approach aims to overcome drug resistance and improve patient outcomes by selectively inhibiting PI3Kα, a key driver in TNBC.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- Triple-negative breast cancer (TNBC) is a fatal malignancy with high metastatic rates.
- Drug resistance and poor patient compliance significantly hinder TNBC treatment development.
- PIK3CA gene mutations drive TNBC by disrupting cell cycle regulation and proliferation, making PI3Kα a key therapeutic target.
Purpose of the Study:
- To discover novel, selective PI3Kα inhibitors for TNBC treatment.
- To explore fragment-based drug discovery and virtual screening for hit-to-lead optimization.
- To identify potent and selective drug candidates with potential for in vitro and in vivo validation.
Main Methods:
- Fragment-based drug discovery using the ChemDiv library.
- Structure-based virtual screening including molecular docking and MMGBSA.
- Induced fit docking (IFD), DFT analysis, and molecular dynamics (MD) simulations.
- Bioisosteric replacement and ADMET analysis for lead optimization.
Main Results:
- Identified two novel moieties, Djh1 and Djh2, as potential PI3Kα inhibitors.
- Optimized Djh1 through bioisosteric replacement, yielding Compounds 10 and 06.
- Compounds 10 and 06 demonstrated excellent efficacy and selectivity for PI3Kα inhibition.
- ADMET analysis indicated favorable properties for Compounds 10 and 06.
Conclusions:
- Fragment-based drug discovery combined with computational methods can yield potent PI3Kα inhibitors.
- Compounds 10 and 06 show significant promise as targeted therapies for TNBC.
- Further in vitro and in vivo studies are warranted to confirm the therapeutic potential of these novel compounds.
