A fifth of all human cancers, including nearly all pancreatic and about half of colorectal cancers, are caused by mutations in a particular enzyme called KRAS. After decades of neglect as an intractable therapeutic target, KRAS is now arguably the most sought-after drug target attracting intense attention from pharmaceutical and academic laboratories alike. Among the major breakthroughs in recent years is the approval by the Food and Drug Administration of Lumakras and Krazati for the treatment of non-small cell lung cancer. These drugs work by irreversibly attaching to a particular KRAS mutant, G12C. Therefore, their use is limited to patients carrying this specific KRAS mutation. Other typ...

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A fifth of all human cancers, including nearly all pancreatic and about half of colorectal cancers, are caused by mutations in a particular enzyme called KRAS. After decades of neglect as an intractable therapeutic target, KRAS is now arguably the most sought-after drug target attracting intense attention from pharmaceutical and academic laboratories alike. Among the major breakthroughs in recent years is the approval by the Food and Drug Administration of Lumakras and Krazati for the treatment of non-small cell lung cancer. These drugs work by irreversibly attaching to a particular KRAS mutant, G12C. Therefore, their use is limited to patients carrying this specific KRAS mutation. Other types of KRAS inhibitors are needed for the more than 80% of patients with other mutations in this gene. Moreover, resistance is emerging against G12C inhibitors. It is therefore important to develop alternative mechanisms and approaches of KRAS inhibition, and multiple KRAS inhibitors that work through distinct mechanisms may be used to improve outcomes and decrease the probability of developing adaptive resistance. In previous CPRIT-funded studies, we have discovered and characterized compounds that either selectively inhibit effector binding or simultaneously inhibit KRAS activation and effector binding. This renewal application proposes to build on these progresses to develop inhibitors that broadly act on KRAS mutants and thereby help a wide spectrum of cancer patients. We will especially focus on compounds that disrupt KRAS-effector interactions and simultaneously inhibit KRAS activation and effector interactions.

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