Abstract
Compound 3144 is a multivalent pan-RAS inhibitor that suppresses tumor growth in vivo.
Major finding: Compound 3144 is a multivalent pan-RAS inhibitor that suppresses tumor growth in vivo.
Approach: Small molecules were designed to target adjacent RAS sites required for protein–protein interactions.
Impact: Structure-based inhibitor design suggests RAS may be a druggable target in patients with cancer.
RAS is a commonly mutated driver in patients with cancer, but developing therapeutic agents targeting RAS has proven challenging. Welsch and colleagues hypothesized that designing compounds that target multiple RAS sites might improve the affinity and selectivity of inhibitors to allow pharmacologic RAS inhibition. Analysis of the structure of the oncogenic KRASG12D mutant found three adjacent sites that could be targeted to block RAS interactions with effector proteins. Virtual screening of small-molecule libraries designed to span two or three of these sites identified candidate multivalent pan-RAS inhibitors that could bind to HRAS, NRAS, and KRAS, and compound 3144 was selected for further study. The ability of 3144 to bind KRASG12D was validated using microscale thermophoresis (MST), isothermal titration, calorimetry, and nuclear magnetic resonance, and MST confirmed that 3144 also binds to wild-type KRAS, HRAS, and NRAS. Compound 3144 inhibited RAS signaling and induced a degree of RAS-dependent lethality in RAS-driven cancer cell lines and mouse embryonic fibroblasts, although it also exhibited some off-target activity. Moreover, this compound was stable in mouse liver microsomes and exhibited acceptable pharmacokinetics when delivered orally, intraperitoneally, or intravenously in mice, supporting further in vivo testing. Compound 3144 reduced the growth of KRASG12D-driven breast cancer xenografts and reduced expression of phospho-ERK, indicating on-target inhibition of KRASG12D. Additionally, 3144 reduced tumor burden in a patient-derived xenograft model of T-cell acute lymphoblastic leukemia. In a mouse model of KRASG12D-driven pancreatic cancer, 3144 reduced RAS signaling, but substantial toxicity resulted due to the genetics of the mouse model used, preventing assessment of antitumor activity. The identification of compound 3144 as an effective pan-RAS inhibitor suggests that multivalent targeting may render RAS and other proteins druggable targets in patients with cancer, although compound optimization will be required to reduce toxicity and improve potency.
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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