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Recent Advances in the Design and Synthesis of Small Molecule Carbonic Anhydrase IX Inhibitors
Pengcheng Lv1, Yinyi Cai1, Jiayi Luo1
1The Joint Research Center of Guangzhou University and Keele Univeristy for Gene Interference and Application, School of Life Science, Guangzhou University, Guangzhou, 510006, People\'s Republic of China.
Abstract:
Human carbonic anhydrase (CA) IX is a tumor-associated protein since it is scarcely present in normal tissues but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. A variety of approaches and design strategies were reported that afford CA IX/XII specific inhibitors and avoid the compromising effects of isoforms-promiscuous compounds. CA IX inhibitors hybrids/conjugates have become an important scaffold to design therapeutic agents with both CA inhibition and anti-cancer effects. In this review, we firstly present an overview of the role of CA IX in hypoxic tumors physiopathology, then provide a comprehensive update on the rational design and synthesis of small molecule CA IX inhibitors discovered since 2019. Also, their structure-activity relationship analysis studies are covered. A brief description of applications for CA IX inhibition in other therapeutic areas is also provided.
Insights
Human carbonic anhydrase IX (CA IX) is a key target in hypoxic tumors. This review details novel small molecule CA IX inhibitors designed since 2019 for anti-cancer therapies.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Human carbonic anhydrase (CA) IX is a tumor-associated protein overexpressed in solid tumors.
- CA IX plays a crucial role in hypoxic tumor survival and metastasis.
- Targeted CA IX inhibition offers a promising therapeutic strategy.
Purpose of the Study:
- To review the role of CA IX in hypoxic tumors.
- To provide an update on the rational design and synthesis of small molecule CA IX inhibitors discovered since 2019.
- To cover structure-activity relationship (SAR) analyses and other therapeutic applications.
Main Methods:
- Literature review of CA IX inhibitors and their design strategies.
- Analysis of SAR studies for newly discovered small molecule inhibitors.
- Overview of CA IX's role in tumor pathophysiology.
Main Results:
- Numerous CA IX/XII specific inhibitors have been developed, avoiding off-target effects.
- CA IX inhibitor hybrids/conjugates serve as scaffolds for dual-action therapeutic agents.
- Recent advancements focus on rational design and synthesis of potent small molecule inhibitors.
Conclusions:
- CA IX is a validated target for anti-cancer drug development, particularly in hypoxic tumors.
- Targeted inhibition of CA IX holds potential for improving cancer treatment outcomes.
- Continued research into CA IX inhibitors may yield novel therapeutic agents for various cancers and other diseases.
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