Recent progress in small molecules targeting the acidic tumor microenvironment.
Targeting the acidic tumor microenvironment shows promise but faces significant challenges in clinical translation and target selectivity.
Where it sits
this study against the rest of the pe 22-28 corpusSummary and findings
The paper reviews recent progress in small molecule inhibitors targeting the acidic tumor microenvironment, focusing on molecular design, mechanisms of action, and preclinical studies. It discusses challenges like metabolic compensation and target selectivity, and reviews acid-targeted delivery strategies. The aim is to inform the development of antitumor drugs with high selectivity and low toxicity.
Abstract
The acidic tumour microenvironment (pHe 6.5-6.9) is sustained by the Warburg effect and pH regulators, such as monocarboxylate transporters 1 and 4, Na+/H + exchanger 1, vacuolar ATPase, and carbonic anhydrases IX and XII. This environment facilitates tumour invasion, immune evasion, and resistance to therapy in solid tumours. Recent advancements in small molecule inhibitors targeting these pathways have demonstrated potential in molecular design, mechanisms of action, and preclinical studies. However, practical applications face challenges, including metabolic compensation, insufficient target selectivity, and clinical translation difficulties. This article reviews the structural design, structure-activity relationships, biological activity, and clinical trial progress of small molecule inhibitors. It also summarises acid-targeted delivery strategies, such as pH-responsive prodrugs and pHLIP peptides. The aim is to highlight the opportunities and challenges in acid-base regulation within the tumour microenvironment and offer insights for developing a new generation of antitumor drugs with high selectivity and low toxicity.
Background
The acidic tumor microenvironment, characterized by a pH of 6.5-6.9, is a result of the Warburg effect and various pH regulators. This environment supports tumor invasion, immune evasion, and therapy resistance. Understanding and targeting this environment is crucial for developing effective antitumor therapies.
Methods
This is a review article that compiles recent advancements in small molecule inhibitors targeting the acidic tumor microenvironment. It covers molecular design, structure-activity relationships, biological activity, and clinical trial progress. The review also discusses acid-targeted delivery strategies.
Results
Not reported in abstract.
Interpretation
The review suggests that while there is potential in targeting the acidic tumor microenvironment, significant challenges remain. These include metabolic compensation and the difficulty in achieving target selectivity. The findings align with existing literature on the complexity of tumor microenvironment targeting.
Key findings
- pHe 6.5-6.9 in tumor microenvironment.
- Targets include monocarboxylate transporters 1 and 4, Na+/H+ exchanger 1, vacuolar ATPase, and carbonic anhydrases IX and XII.
- Challenges include metabolic compensation and insufficient target selectivity.
Limitations
- Challenges in clinical translation.
- Insufficient target selectivity.
- Metabolic compensation issues.