Targeting Cyclin E Overexpression: The Therapeutic Potential of APR-1051 in Cancer Treatment

In preclinical studies, APR-1051, a novel WEE1 inhibitor (WEE1i), has shown reduced off-target effects on PLK1, PLK2, and PLK3 kinases and has effectively suppressed the growth of tumors with high levels of CCNE1 in xenograft models. This new compound has demonstrated a low IC50 value for WEE1 and has the capacity to restrict the proliferation of a range of cancer cell lines. Notably, the compound's genotoxicity is mitigated by the presence of PLK1 inhibitors, indicating that other WEE1 inhibitors with off-target effects on PLK1 might be less effective and could cause adverse side effects.

APR-1051 has been particularly effective against breast and ovarian cancer cells that overexpress Cyclin E, suggesting Cyclin E as a potential indicator for APR-1051 therapy. The treatment regimen of APR-1051 that significantly reduces CCNE1-amplified ovarian cancer in mice is well-tolerated, with no significant impact on red blood cell and platelet counts after a month-long treatment. Moreover, APR-1051 inhibits WEE1 at an IC50 that is significantly lower than that for hERG potassium channel inhibition, indicating a low risk of cardiotoxicity.

As APR-1051 advances through IND-enabling studies, these results highlight its potential as a new WEE1i for treating cancers with overexpressed Cyclin E. This drug candidate offers a promising therapeutic approach by exploiting synthetic lethality with Cyclin E overexpression, while minimizing off-target effects and hematological toxicities associated with other WEE1 inhibitors.