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Efforts to Develop KRAS Inhibitors.

Matthew Holderfield¹

¹NCI-Ras Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland 21702.

Cold Spring Harbor Perspectives in Medicine

|November 5, 2017

Summary

This summary is machine-generated.

Targeting KRAS mutations in cancer has been challenging, but new drug discovery methods offer hope. This review explores historical and emerging strategies for developing KRAS inhibitors.

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Area of Science:

Oncology
Drug Discovery
Molecular Biology

Background:

KRAS mutations are prevalent in human cancers, driving significant unmet medical needs.
Targeting oncogenic KRAS proteins with small molecules has historically proven difficult, leading to the 'undruggable' classification.
Decades of research have yielded limited success in developing effective KRAS inhibitors.

Purpose of the Study:

To review historical attempts at developing RAS (Rat Sarcoma virus) pathway inhibitors.
To highlight recent advancements and promising strategies for targeting KRAS.
To re-evaluate the feasibility of targeting KRAS in cancer therapy.

Main Methods:

In silico screening
Fragment-based drug design
Disulfide tethered screening
Exploration of emerging RAS biology themes

Main Results:

Despite historical challenges, recent technological and biological insights are revitalizing efforts.
New approaches are demonstrating potential for identifying novel KRAS inhibitors.
The field is reconsidering KRAS as a druggable target.

Conclusions:

Recent progress in drug discovery technologies and understanding of RAS biology offers renewed optimism for targeting KRAS.
Emerging strategies show promise in overcoming previous hurdles in developing effective KRAS inhibitors for cancer treatment.