Small Molecule Activators Of GTP Hydrolysis For Mutant Ras-Driven Cancer

Patent Status

Patent Pending

Brief Description

Oncogenic mutations in the Ras family of small GTPases (like K-Ras, H-Ras, and N-Ras) are major drivers of many human cancers, yet they remain one of the most challenging targets in oncology. These mutations often trap the Ras protein in its active, GTP-bound state, leading to continuous, unchecked cell proliferation. To address this, UC Berkeley researchers have developed a novel class of Small Molecule Activators of GTP Hydrolysis for Mutant Ras-driven Cancer.

These compounds accelerate the natural, but often disabled, guanosine triphosphate (GTP) hydrolysis process in mutant Ras, essentially forcing the protein back into its inactive, GDP-bound state. The compounds utilize a modular, "plug-and-play" structure. This modular platform is unique in its ability to reactivate the intrinsic GTPase function of mutant Ras, offering a promising, direct-acting therapeutic strategy against previously intractable Ras-driven cancers.

Suggested uses

• As a therapeutic agent for various Ras-driven cancers, including pancreatic, colorectal, and lung cancer.

• Development of precision medicines specifically targeting different Ras oncogenic mutants (e.g., K-Ras G12D, G12V) through modification of the targeting moiety (R).

• Drug design platform for accelerating GTP hydrolysis in other medically relevant GTPases implicated in disease.

• Used in combination therapies with existing chemotherapy or immunotherapy regimens to enhance efficacy against Ras-mutated tumors.

Advantages

• Directly addresses the fundamental mechanism of Ras oncogenicity by reactivating the protein's native GTPase function, rather than merely inhibiting downstream signaling.

• Provides a modular, plug-and-play drug design platform, allowing for rapid synthesis and screening of analogs with varied specificity for different Ras mutants and improved pharmacokinetic properties.

• The mechanism is catalytic, meaning one small molecule can facilitate the hydrolysis of multiple GTP molecules, potentially leading to higher efficacy compared to simple stoichiometric inhibitors.

• Offers a novel approach to targeting Ras, which has historically been considered "undruggable," opening up new avenues for precision oncology.

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