LAUSR

Somatic mutations of calreticulin (CALR)have been identified as one of the main disease drivers of myeloproliferative neoplasms (MPNs), suggesting that developing drugs targeting mutant CALR is of great significance. Site-directed mutagenesis in the N-glycan binding domain (GBD)abolishes the ability of mutant CALRto oncogenically activate the thrombopoietin receptor (MPL).We thus hypothesized that a small molecule targeting the GBD might inhibit the oncogenicity of the mutant CALR. Using an in-silico molecular docking study, we identified candidate binders to the GBD of CALR. Further experimental validation of the hits identified a group of catechols inducing selective growth inhibitory effect on cells that depend on oncogenic CALRs for survival and proliferation. Apoptosis-inducing effects by the compound were significantly higher in the CALR mutated cells than in CALR wild type cells. Additionally, knockout or C-terminal truncation of CALR abolished the drug hypersensitivity in CALR mutated cells. We experimentally confirmed the direct binding of the selected compound to CALR, the disruption of the mutant CALR-MPL interaction, the inhibition of the JAK2-STAT5 pathway, and reduction of intracellular level of mutant CALR upon the drug treatment. Our data conclude that small molecules targeting the GBD of CALR can selectively kill CALR mutated cells by disrupting the CALR-MPL interaction and inhibiting the oncogenic signaling.