Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity

Area of Science:

• Molecular oncology
• Cancer cell biology
• Drug discovery

Background:

• Precise control of E2F1 activity is crucial for cancer cell proliferation; excessive E2F1 activity can trigger apoptosis.
• Small cell lung cancer (SCLC) often exhibits high E2F1 activity, presenting a therapeutic vulnerability.

Purpose of the Study:

• To develop cell-permeable and bioavailable macrocycles targeting cyclin A/B interactions.
• To investigate the mechanism of action and therapeutic potential of these macrocyclic inhibitors in SCLC.

Main Methods:

• Development of cell-permeable macrocycles inhibiting RxL-mediated interactions of cyclin A and cyclin B.
• Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens to identify resistance mechanisms.
• Base editor screens to analyze cyclin B variants affecting inhibitor response.
• Evaluation of orally bioavailable macrocycles in patient-derived xenograft models of SCLC.

Main Results:

• Macrocyclic inhibitors (cyclin A/Bi) selectively kill SCLC cells by blocking cyclin A/B interactions.
• Cyclin A/Bi induce apoptosis through spindle assembly checkpoint (SAC) activation, dependent on cyclin B and Cdk2.
• Inhibitors hyperactivate E2F1 and cyclin B, leading to mitotic cell death.
• Orally bioavailable cyclin A/Bi demonstrated robust tumor growth inhibition in chemotherapy-resistant SCLC xenografts.

Conclusions:

• Cyclin A/Bi induce apoptosis in cancers with high E2F activity via novel gain-of-function mechanisms.
• The findings suggest cyclin A/Bi as a promising therapeutic strategy for SCLC and other E2F1-driven cancers.