Since half of all cancer patients receive radiation therapy (RT), enhancing the effectiveness of RT is an unmet need. Gilmer et al. characterize a novel compound, XRD-0394, that exhibits selective and potent inhibition of two DNA damage-response kinases, ATM and DNA-PKcs. This orally bioavailable compound demonstrates significant radiosensitizing activity, in vitro and in vivo, in multiple cancer models. In addition, synthetic lethality in BRCA-mutant tumors and synergy with PARP inhibitors and with topoisomerase I inhibitors were demonstrated in vitro. These results provide a rationale for future clinical trials with XRD-0394 in combination with RT, PARP inhibitors and targeted delivery of topoisomerase I inhibitors.
Upregulation of MYC is frequently associated with unfavorable patient survival. Here, Chang and colleagues discovered 6K465, a small molecule that effectively lowers c-MYC/N-MYC levels and inhibits Aurora A kinase. Further development transformed 6K465 into the prodrug DBPR728, which exhibited enhanced oral bioavailability and prolonged half-life...
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