For years, the KRAS oncogene was considered a key cancer driver but impossible to target with drugs. Through resilient investigation, scientists recently developed effective therapies against it, proving that even long-held beliefs about 'undruggable' targets can be overturned with persistence.

Unlike earlier G12C-specific "RAS-off" drugs that lock KRAS in an inactive state, new "RAS-on" inhibitors form a tri-complex with an active form of RAS and an endogenous protein. This novel mechanism enables targeting of a much broader spectrum of RAS mutations, representing a significant breakthrough for treating pancreatic cancer.

A new class of KRAS inhibitors targets the active 'on-state' of the protein, a departure from earlier drugs that targeted the inactive 'off-state'. These 'tri-complex inhibitors' use a chaperone protein to bind to the active GTP-bound KRAS, preventing downstream signaling and creating a new therapeutic avenue.

Instead of directly blocking the mutated KRAS protein, daraxin racid acts as a 'molecular glue.' It binds to a separate chaperone protein, and this new complex then disables the mutated KRAS protein. This indirect, novel mechanism of action is a breakthrough for targeting a protein that has been notoriously difficult to drug.

Unlike traditional small molecules that need a pocket on a target protein, molecular glues work by changing the surface of an E3 ligase. This modified surface then perfectly matches and binds the target protein, enabling its degradation without requiring a direct drug-to-target binding site.

Instead of targeting the final protein, Remix develops small molecules that intervene during pre-mRNA processing. This novel approach allows them to inhibit historically difficult drug targets like MYB, a transcription factor with no obvious binding sites, by preventing the disease-driving protein from ever being made.

The concept of an "undruggable" target is a misnomer, according to Pacesa. Any failure to create a binder for a specific protein site is a limitation of the current design method or modality, not an intrinsic property of the target. He posits that, with the right approach, a binder can be designed for any site.

To combat resistance to drugs like Osimertinib, Blossom Hill designed a molecule potent against the C797S resistance mutation and equally potent against original mutations. This dual efficacy, preventing cancer evolution, is central to their promising clinical results and is a key design principle for durable cancer therapies.

By focusing on the phenotypic outcome (cellular stress) rather than a predefined target, Soleil's platform can identify small molecules that modulate proteins considered undruggable by conventional means. Their lead oncology candidate, for example, modulates CCAP2, demonstrating the platform's ability to find novel biology and expand the druggable space.