Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma

Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation DNA. MTH1 is highly upregulated tumor biopsies from patients with diffuse large (DLBCL) and Burkitt lymphoma, hence confirming rationale targeting MTH1. Here, we tested the efficacy karonudib vitro preclinical models. Using range cell lines, strongly reduced viability at concentrations well tolerated by activated normal B cells. In cells, increased incorporation 8-oxo-dGTP into DNA, prominently induced prometaphase arrest apoptosis due failure spindle assembly. knockout lines were less sensitive karonudib-induced apoptosis, displaying cycle phenotype similar wild type indicating dual inhibitory role drug. potent as single agent two different xenograft models, including ABC DLBCL patient derived xenograft, leading prolonged fully controlled growth. Together, our findings provide further clinical testing lymphoma.