How KRAS Became Druggable: Kevan Shokat and the Pocket That Opened a New Era of RAS Drugs
For decades, researchers knew KRAS was one of cancer’s most important drivers. KRAS mutations are found across cancers including lung, pancreatic and colorectal cancer. Yet knowing KRAS was helping a cancer grow did not give researchers a medicine capable of stopping it. KRAS became known as “undruggable.”
Then chemist and cancer researcher Kevan Shokat, PhD, and his colleagues found a way in.
In 2013, Shokat’s team reported that KRAS G12C contained a previously unrecognized pocket that could be exploited with small molecules. That discovery gave researchers a direct way to interfere with mutant KRAS and helped launch a new era of RAS drug development.
Finding a Way Into KRAS
RAS proteins function like molecular switches.
When RAS is bound to GTP, the switch is ON and sends signals that help cells grow. When it is bound to GDP, the switch is OFF and that signaling is reduced. Cancer causing RAS mutations can disrupt this normal cycle and keep growth signaling active.
For years, researchers struggled to attack KRAS directly. Its surface appeared to offer few useful places for a small molecule drug to bind.
Shokat’s team focused on KRAS G12C. In this variant, glycine at position 12 of KRAS is replaced by cysteine. That cysteine created a chemical foothold.
The researchers developed compounds capable of attaching to it and uncovered a previously unrecognized pocket beneath a region of KRAS called switch II.
Suddenly, KRAS had something researchers had struggled to find: a place to get in.
Their compounds bound KRAS G12C and favored the inactive, GDP bound form of the protein. Shokat and colleagues published the discovery in Nature in 2013.
The discovery did more than identify one promising compound. It showed that mutant KRAS could be attacked directly.
From G12C to a New Generation of RAS Drugs
Years of additional research and medicinal chemistry followed.
In 2021, sotorasib became the first FDA approved treatment to directly target KRAS G12C in lung cancer. Adagrasib followed, adding another direct KRAS G12C treatment and further establishing KRAS as a druggable cancer target.
The significance quickly grew beyond G12C.
That first foothold changed what researchers were willing to attempt. Research programs began pursuing other KRAS variants, broader KRAS strategies and different states of the RAS protein.
One of the most important newer approaches targets RAS while the molecular switch is ON.
Daraxonrasib is a RAS (ON) multi-selective inhibitor that works differently from the original G12C inhibitors. Rather than depending on the cysteine unique to G12C, it targets active RAS across multiple RAS variants.
On August 26, 2026, the FDA approved daraxonrasib for adults with metastatic pancreatic adenocarcinoma who had received at least one prior systemic therapy or who were not candidates for multiagent systemic therapy.
The journey from finding a pocket in KRAS G12C to targeting active RAS across multiple variants represents a fundamental expansion of what is possible in RAS drug development.
More Than a Decade Later
On September 26, 2026, Shokat received the $1 million Stephenson Global Prize for pancreatic cancer research at the AACR Conference on Pancreatic Cancer in San Diego.
The recognition comes more than a decade after the discovery that helped change how researchers approached one of cancer’s most difficult targets.
UCSF reports that more than 60 additional drugs targeting the RAS family are now in development. What began with a chemical foothold in KRAS G12C has become an expanding field of RAS drug discovery.
Why This Matters for People With KRAS Cancer
The science also explains why knowing the exact KRAS variant matters.
G12C provided the first direct opening. Research now reaches additional KRAS variants and broader RAS strategies, including approaches aimed at G12D, G12V, multiple KRAS variants and active RAS.
The questions become more specific:
Which KRAS? Which RAS? Which cancer?
Testing is the first step. People also need the exact result so they can understand whether an approved treatment, clinical trial or emerging strategy may be relevant to them.
See the KRAS Science Up Close In a KRAS Kickers conversation, Kevan Shokat sits down with founder Terri Conneran and uses a three dimensional model of KRAS to explain the science and where RAS research is heading.
Today, direct KRAS inhibitors, RAS ON inhibitors and other emerging approaches are expanding what researchers can pursue across lung, pancreatic, colorectal and other RAS driven cancers.
At KRAS Kickers, our work is to help people understand what they have, what the science means and where the next opportunity may be.
Knowledge. Research. Advocacy. Survivorship.
Hope shared is hope multiplied.
Explore KRAS education, research, advocacy and clinical trial resources at KRAS Kickers.
