Abstract
The small molecule APS-2-79 stabilizes an inactive form of the MAPK scaffold KSR to repress RAS signaling.
Major finding: The small molecule APS-2-79 stabilizes an inactive form of the MAPK scaffold KSR to repress RAS signaling.
Clinical relevance: APS-2-79 synergizes with MEK inhibitors to improve their efficacy in KRAS mutant cells.
Impact: Targeting both enzymatic and scaffolding activity in the RAS–MAPK pathway may inhibit RAS-driven tumors.
RAS genes are frequently mutated in cancer, but therapeutic targeting of RAS has proven challenging, with drug development efforts largely focusing on the RAS effectors RAF, MEK, and ERK. A MAPK scaffolding protein, kinase suppressor of ras (KSR), which is a pseudokinase and noncatalytic regulator of the core RAS pathway signaling enzymes, has been suggested as an additional possible therapeutic target to disrupt RAS signaling. Dhawan, Scopton, and Dar noted KSR mutations that selectively inhibit mutant, but not wild-type, RAS from forward genetic screens in flies and worms and discovered that many of the mutations were adjacent to the KSR ATP-binding pocket, leading them to hypothesize that the interaction between KSR and RAF or MEK might be blocked by ligands that bind the KSR ATP-binding pocket. A collection of structurally diverse kinase inhibitors was screened to identify small molecules that bind the ATP-binding pocket of KSR2–MEK1 complexes, resulting in the identification of the quinazoline–biphenyl ether compound APS-1-68-2. Further optimization resulted in APS-2-79, a compound that potently reduced KSR-dependent MEK and ERK activation and mimicked the KSR mutant alleles that inhibit the oncogenic signaling of mutant RAS. Crystal structures indicated that APS-2-79 antagonized MEK phosphorylation by RAF by binding the KSR active site within the KSR2–MEK1 complex and stabilizing the inactive state of KSR2. Moreover, stabilization of the KSR inactive state with APS-2-79 enhanced the effects of MEK inhibitors in KRAS-mutant cells. The identification of an inactive form of KSR stabilized by a small molecule indicates that KSR targeting may indirectly suppress RAS signaling, and the combined effects of KSR and MEK inhibition suggest that dual targeting of enzymatic and scaffold proteins may improve RAS pathway suppression.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
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