一种NVL小分子抑制剂通过阻断核糖体生物合成抑制肿瘤生长

Our research program integrates phenotypic screening with a tunable forward-genetics platform engineered to identify anticancer small molecules and their novel molecular targets. Using this approach, we identified nuclear valosin-containing protein-like (NVL), a hexameric AAA+ ATPase required for large ribosomal subunit (60S) assembly, as the target of a dibenzothiazepinone, MM17. Cryo-EM reconstructions of NVL bound to a substrate analog mimic reveal two MM17 docking sites within the hexameric assembly, with resistance mutations clustering around the ligand binding site. NVL inhibition disrupts 60S biogenesis and stabilizes p53 through MDM2, leading to cell cycle arrest or apoptosis, in the absence of DNA damage. Cancer cells upregulate ribosome production to sustain the high protein synthesis demands of unchecked proliferation, making ribosome biogenesis an attractive therapeutic target. Notably, inhibition of ribosome biogenesis-rather than induction of DNA damage-has recently been identified as a major mechanism underlying widely used chemotherapies such as 5-FU and oxaliplatin. To assess the therapeutic potential of selectively targeting ribosome biogenesis by blocking NVL, we engineered a degron system (NVL-AID) in which administration of 5-Phenyl-indole-3-acetic acid (Ph-IAA) dose dependently degrades the endogenous NVL protein in a colorectal cancer cell line. Degradation of NVL phenocopied the effects of MM17 treatment on the induction of p53, the blockade of ribosome assembly, and on the inhibition of cell growth. Moreover, daily Ph-IAA administration for two weeks effectively suppressed the growth of established NVL-AID xenograft tumors. A more potent and bioavailable MM17 analog, MM927, suppressed tumor growth in mouse models of colorectal cancer through direct NVL targeting, supporting the pharmacological inhibition of ribosome assembly as a cancer vulnerability. Together, these findings validate NVL as a therapeutic target and set a benchmark for the efficacy of small-molecule NVL inhibitors. Current efforts are focused on lead optimization to nominate advanced, orally bioavailable NVL inhibitors that are tested head-to-head with target degradation (NVL-AID) to maximize efficacy. To characterize the on-target toxicities of candidate leads, we developed a CRISPR-engineered, compound-resistant mouse model. Collectively, these tools will enable us to characterize the consequences of inhibiting this novel cancer target in normal tissues and to establish the therapeutic index of optimized NVL inhibitors to support their clinical development.