Progress in targeting RAS with small molecule drugs

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.