From science fiction to scientific reality in the quest to target KRAS

KRAS mutations occur in around one in four newly diagnosed lung cancers2,3, with KRAS G12C linked to poorer outcomes for patients3,4. For Hans Purkey and his multidisciplinary team, the challenge was to find a different way to target it.

In a conference room buzzing with ambitious ideas, a colleague leaned back and whispered loudly a phrase that made the whole research team laugh: "This entire project is science fiction." They laughed because everyone in that room knew the daunting reality: KRAS was considered one of the toughest targets in cancer research.

In certain lung cancers, specific mutations like KRAS G12C prolong the protein’s active state – acting like a jammed accelerator pedal that keeps growth signals permanently switched on to drive uncontrolled cell growth5,6. For Genentech Research and Early Development (gRED) Senior Director, Hans Purkey, who has spent his career bridging computational chemistry and drug discovery, the work also carried a personal connection through his own family’s experience of cancer.

Yet in the early stages, progress felt agonisingly slow. The team spent six long months "wandering in the wilderness”, where nearly 99 percent of their chemical tweaks did not make compounds better than where they had started.

Hans Purkey
Senior Director & Senior Principal Scientist, Computational Drug Discovery at Genentech

Targeting the "back pocket"

The answer lay in a landmark 2013 discovery by academic researchers at the University of California, San Francisco. They revealed that the inactive KRAS G12C protein features a hidden, transient pocket – known as the Switch-II pocket – that occasionally opens allowing a small molecule to slip inside and lock the mutant protein in an inactive state. While other research groups were advancing early molecules into clinical trials, Purkey’s team saw an opportunity to engineer a candidate with even greater precision – tailored to fit as snugly and selectively as possible into this pocket and shut down the continuous signals driving cancer cell growth1.

Combining computational design and other methods of modern medicinal chemistry, Purkey and his team spent several years designing molecules to bind the Switch-II pocket with high affinity, by optimising the interactions deep inside the pocket. By ensuring the molecule fits as snugly as possible inside the pocket before irreversibly locking in place, the team aimed to develop a compound with high biochemical potency in their early research.

By engineering a novel structural piece to slip into a region of Switch-II, nicknamed the “back pocket”, they created a candidate that altered the trajectory of their research. In the summer of 2018, the first activity test results arrived for this new molecule. In preclinical laboratory assays, this candidate demonstrated ten times the potency of any molecule the team had previously synthesised1. Worried that this could be an experimental mistake, Purkey ordered a repeat measurement the following week, just to rule out a testing error. When the results came back confirmed, the team knew they had found a new direction to pursue and accelerated its advancement.

An elegant two-step lock

The secret behind this change in laboratory potency was the molecule's architecture. At the molecular level, the team’s design centred on a two-step mechanism. First, the molecule fits tightly into the binding pocket through highly optimised interactions. Second, it rapidly forms a permanent bond with the G12C mutation, locking the protein in its inactive state. Because cancer cells can continuously produce new KRAS G12C proteins, the team designed the molecule to bind tightly and react rapidly and selectively1.

Science in the service of patients

For Purkey, engineering a molecule designed to target cancer signalling was never just a biophysical puzzle – it was a personal mission. Earlier in his career, while visiting a family member in hospital, a physician told Purkey that while doctors may treat thousands of patients in a lifetime, a scientist who discovers a highly efficient medicine has the opportunity to touch many more lives. Today, as science continues to move forward, his project stands as a testament to human persistence. It serves as a powerful reminder of how curiosity, collaboration, and courage can transform decades of scientific doubt into new avenues of clinical research for patients facing cancer.