Insights into direct KRAS inhibition strategies for cancer treatment
Tong Li1, Chenglei Gu1, Chen Zhou2
1School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Abstract:
KRAS is the most commonly mutated isoform in RAS-driven cancers. In the early stage, KRAS was deemed as an "undruggable" cancer target due to the lack of suitable binding pockets. With the development of KRAS inhibitors in recent years, strategies that directly suppress oncogenic KRAS have achieved significant breakthroughs. In this review, we summarize recent advances in direct small-molecule KRAS inhibitors used for cancer therapy, highlighting their medicinal chemistry optimization processes. Moreover, new PROTACs targeting the KRAS mutation are also presented. Additionally, we put forward the challenges and prospects for the development of future KRAS inhibitors.
Insights
Directly targeting KRAS mutations in cancer therapy has seen major breakthroughs with new small-molecule inhibitors and Proteolysis Targeting Chimeras (PROTACs). This review highlights recent advances, challenges, and future prospects for KRAS inhibitors.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- KRAS mutations are prevalent in various cancers, historically posing a significant therapeutic challenge due to the lack of druggable targets.
- Recent advancements have shifted the paradigm, enabling direct targeting of oncogenic KRAS.
- Small-molecule inhibitors and novel modalities like PROTACs are emerging as promising strategies.
Purpose of the Study:
- To review recent progress in the development of direct small-molecule KRAS inhibitors for cancer treatment.
- To present novel Proteolysis Targeting Chimeras (PROTACs) designed to target KRAS mutations.
- To discuss current challenges and future directions in KRAS inhibitor research.
Main Methods:
- Literature review of recent studies on KRAS inhibitors.
- Analysis of medicinal chemistry optimization strategies for small-molecule KRAS inhibitors.
- Overview of emerging PROTAC technologies targeting KRAS.
Main Results:
- Significant breakthroughs have been achieved with small-molecule inhibitors directly suppressing oncogenic KRAS.
- New PROTACs targeting KRAS mutations are being developed, offering alternative therapeutic approaches.
- Medicinal chemistry efforts have successfully optimized KRAS inhibitors.
Conclusions:
- Directly targeting KRAS is a viable and advancing strategy in cancer therapy.
- Small-molecule inhibitors and PROTACs represent key developments in this field.
- Continued research is essential to overcome challenges and realize the full potential of KRAS inhibitors.
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