Aprea Therapeutics, Inc. announced updated preclinical data supporting development of the Company's WEE1 inhibitor candidate, ATRN-1051, for the treatment of ovarian cancer. The preclinical and in vitro data suggest that the selective properties of ATRN-1051 may make it a more efficacious cancer therapy than the other WEE1 inhibitors in development. Importantly, ATRN-1051 is a highly potent and selective inhibitor of WEE1 that does not significantly affect off-target PLK1, PLK2 and PLK3, a family of kinases that promote M phase entry, a critical phase in the cell cycle.

Such off-targeting of the PLK family has been a challenge to other WEE1 inhibitors in the class. Evidence generated by Aprea suggests that off-target inhibition of PLK1 substantially limits the ability of WEE1 inhibitors to cause genotoxicity, the proposed mechanism by which WEE1 inhibitors act as cancer therapeutics. The preclinical research of ATRN-1051 in ovarian cancer also shows an increased expression of cyclin E1, or CCNE1.

CCNE1 amplification, which is associated with platinum resistance and poor survival, has been shown to be a reliable predictive biomarker of response to WEE1 inhibition. As part of the preclinical studies with ATRN-1051, the Company conducted cell culture and CDX mouse model studies using the CCNE1-normal and CCNE1-amplified ovarian cancer cell lines to show that low doses of ATRN-1051 completely suppress the growth of CCNE1-amplified ovarian cancer cells and tumors. In addition to the anti-tumor activity, the preclinical studies of ATRN-1051 indicate improved AUC pharmacokinetic properties compared to other WEE1 inhibitors, with the low dose of ATRN-1051 showing a similar AUC as higher doses of other WEE1 inhibitors.

WEE1 kinase is a key regulator of multiple phases of the cell cycle, most prominently in progression from G1 to S phase and S to M phase through inhibitory phosphorylation of CDK2 and CDK1, respectively. Thus, when WEE1 is inhibited, both G1-S and S-M checkpoints are abrogated, leading to premature S-phase and M-phase entry. Notably, the replication stress caused by CCNE1 overexpression is transformed into toxic levels of double stranded breaks and cancer cell death when WEE1 is inhibited.

The Company believes that CCNE1 gene amplification or high CCNE1 protein expression is a potential predictive biomarker of ATRN-1051 efficacy.