Hybridization-based discovery of novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors
Changqun Liu1, Yuening Cao1, Yi Zuo1
1State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Introduction:
Phosphatidylinositol 3-kinases (PI3Ks) overexpression can elicit cellular homeostatic dysregulation, which further contributes to tumorigenesis, with PI3Kα emerging as the most prevalent mutant isoform kinase among PI3Ks. Therefore, selective inhibitors targeting PI3Kα have attracted considerable interest in recent years. Molecular hybridization, with the advantage of simplified pharmacokinetics and drug-drug interactions, emerged as one of the important avenues for discovering potential drugs.
Objectives:
This study aimed to construct PI3Kα inhibitors by hybridization and investigate their antitumor activity and mechanism.
Methods:
26 quinazoline-2-indolinone derivatives were obtained by molecular hybridization, and their structure-activity relationship was analyzed by MTT, in vitro kinase activity and molecular docking. The biological evaluation of compound 8 was performed by transwell, flow cytometry, laser scanning confocal microscopy, Western blot, CTESA and immunohistochemistry.
Results:
Here, we employed molecular hybridization methods to construct a series of quinazoline-2-indolinone derivatives as PI3Kα selective inhibitors. Encouragingly, representative compound 8 exhibited a PI3Kα enzymatic IC50 value of 9.11 nM and 10.41/16.99/37.53-fold relative to the biochemical selectivity for PI3Kβ/γ/δ, respectively. Moreover, compound 8 effectively suppressed the viability of B16, HCT116, MCF-7, H22, PC-3, and A549 cells (IC50 values: 0.2 μM ∼ 0.98 μM), and dramatically inhibited the proliferation and migration of NSCLC cells, as well as induced mitochondrial apoptosis through the PI3K/Akt/mTOR pathway. Importantly, compound 8 demonstrated potent in vivo anti-tumor activity in non-small cell lung cancer mouse models without visible toxicity.
Conclusions:
This study presented a new avenue for the development of PI3Kα inhibitors and provided a solid foundation for novel QHIDs as potential future therapies for the treatment of NSCLC.
Insights
Researchers developed novel quinazoline-2-indolinone derivatives as selective PI3Kα inhibitors. Compound 8 showed potent antitumor activity in vitro and in vivo, offering a new therapeutic avenue for non-small cell lung cancer (NSCLC).
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Pharmacology
Background:
- Overexpressed phosphatidylinositol 3-kinases (PI3Ks), particularly PI3Kα, drive tumorigenesis and cellular dysregulation.
- Selective PI3Kα inhibitors are of significant interest for cancer therapy.
- Molecular hybridization offers a strategy to develop novel drug candidates with improved pharmacokinetic profiles.
Purpose of the Study:
- To design and synthesize novel PI3Kα inhibitors using molecular hybridization.
- To evaluate the antitumor activity and elucidate the mechanism of action of these novel compounds.
- To identify lead compounds for potential non-small cell lung cancer (NSCLC) therapy.
Main Methods:
- Synthesis of 26 quinazoline-2-indolinone derivatives via molecular hybridization.
- Structure-activity relationship analysis using MTT assays, in vitro kinase activity, and molecular docking.
- Comprehensive biological evaluation of the lead compound (compound 8) including cell viability, proliferation, migration, apoptosis assays, and in vivo studies in NSCLC mouse models.
Main Results:
- Compound 8 demonstrated highly selective inhibition of PI3Kα with an IC50 of 9.11 nM and significant selectivity over other PI3K isoforms.
- Compound 8 effectively inhibited the viability of various cancer cell lines (IC50: 0.2 μM–0.98 μM).
- Compound 8 suppressed NSCLC cell proliferation and migration, induced mitochondrial apoptosis via the PI3K/Akt/mTOR pathway, and showed potent in vivo anti-tumor efficacy with no apparent toxicity.
Conclusions:
- The study successfully developed novel quinazoline-2-indolinone derivatives as potent and selective PI3Kα inhibitors.
- Compound 8 represents a promising therapeutic candidate for NSCLC treatment.
- This work establishes a new strategy for developing PI3Kα inhibitors and provides a foundation for future drug development.
