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Updated: Jan 30, 2026

A Rapid and Quantitative Fluorimetric Method for Protein-Targeting Small Molecule Drug Screening

A Rapid and Quantitative Fluorimetric Method for Protein-Targeting Small Molecule Drug Screening

Published on: October 16, 2015

Progress in targeting RAS with small molecule drugs.

Frank McCormick¹

¹UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA and Frederick National Laboratory for Cancer Research, Frederick, MD, USA frank.mccormick@ucsf.edu.

The Biochemical Journal

|February 2, 2019

Summary

Targeting oncogenic RAS proteins, traditionally undruggable, is advancing. Small molecules targeting KRAS G12C are in trials, overcoming challenges in RAS protein specificity for cancer therapy.

Keywords:

G-proteins KRAS oncognes

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Area of Science:

Oncology
Molecular Biology
Drug Discovery

Background:

RAS proteins, including KRAS, are historically considered undruggable due to the absence of a conventional active site for small molecule binding.
Oncogenic KRAS mutations are prevalent in many cancers, making KRAS a significant therapeutic target.
RAS proteins share structural similarities, posing challenges for developing specific inhibitors.

Purpose of the Study:

To review the progress and challenges in developing small molecule inhibitors targeting RAS proteins, with a focus on KRAS.
To highlight the emergence of novel drug discovery technologies enabling the targeting of previously undruggable proteins.

Main Methods:

Review of preclinical and clinical data for small molecules targeting RAS proteins.
Analysis of the biochemical properties and structural similarities of RAS isoforms and family members.
Discussion of new drug discovery technologies facilitating the development of RAS-targeted therapies.

Main Results:

Small molecules targeting the KRAS G12C mutation are progressing through preclinical and clinical trials.
Compounds targeting other RAS proteins at distinct sites are in early-stage development.
Despite challenges in specificity due to RAS isoforms and family member similarities, significant scientific progress is being made.

Conclusions:

Targeting RAS proteins, once considered undruggable, is now a reality with emerging small molecule inhibitors.
Advancements in drug discovery technologies are crucial for overcoming the complexities of RAS-targeted cancer therapy.
KRAS remains a primary focus due to its high incidence in cancer, with ongoing efforts to achieve specificity.