Somatic mutations of calreticulin (CALR) have been identified as a main disease 
driver of myeloproliferative neoplasms, suggesting that development of drugs 
targeting mutant CALR is of great significance. Site-directed mutagenesis in the 
N-glycan binding domain (GBD) abolishes the ability of mutant CALR to 
oncogenically activate the thrombopoietin receptor (MPL). We therefore 
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 a selective growth 
inhibitory effect on cells that depend on oncogenic CALR 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 eliminated drug hypersensitivity in 
CALR-mutated cells. We experimentally confirmed the direct binding of the 
selected compound to CALR, disruption of the mutant CALR-MPL interaction, 
inhibition of the JAK2-STAT5 pathway, and reduction at the intracellular level 
of mutant CALR upon drug treatment. Our data indicate that small molecules 
targeting the GBD of CALR can selectively kill CALR-mutated cells by disrupting 
the CALR-MPL interaction and inhibiting oncogenic signaling.