Cyclin A/B RxL-IN-2

Cyclin A/B RxL-IN-2 is a macrocyclic peptide Cyclin A/B inhibitor with oral bioavailability. It exhibits an IC50 of 0.05 μM and a Kd of 2.7 nM for Cyclin A, and an IC50 of less than 0.02 μM and a Kd of 1.0 nM for Cyclin B. This compound competitively binds to the hydrophobic pocket (HP) of Cyclin A/B, blocking their interaction with substrate RxL motifs, inducing replication stress, DNA damage, mitosis, and apoptosis in E2F overexpressing cells. In NCI-H69 and NCI-H446 small cell lung cancer xenograft models, Cyclin A/B RxL-IN-2 demonstrates tumor growth inhibition and regression, making it useful for related small cell lung cancer research.

Cyclin A/B RxL-IN-2 (Compound 33) is a potent and selective binder of Cyclin A and Cyclin B, with IC₅₀ values of 0.050 μM and <0.02 μM, and SPR Kd values of 2.7 nM and 1.0 nM, respectively, while its affinity for Cyclin E is reduced by more than 12-fold. This compound effectively inhibits the proliferation of small cell lung cancer (SCLC) cell lines NCI-H1048, NCI-H446, and NCI-H69, with GI₅₀ values of 0.015 μM, 0.042 μM, and 0.004 μM, over 3 and 5 days in WI-38 cells and the SCLC cell lines, respectively, and shows significantly lower activity in non-transformed WI-38 fibroblasts by more than 1270-fold.

Cyclin A/B RxL-IN-2 (Compound 33), administered orally at doses of 25-50 mg/kg twice daily for 14 days, demonstrates a dose-dependent inhibition and reduction of tumor growth in the NCI-H69 small cell lung cancer (SCLC) xenograft model, with a tumor growth inhibition rate (TGI) of 53% at 25 mg/kg twice daily, and a tumor regression rate of 40% at 50 mg/kg twice daily. In the NCI-H446 small cell lung cancer xenograft model, oral administration of 25-100 mg/kg of Cyclin A/B RxL-IN-2, twice or three times daily for 14 days, shows dose-dependent tumor growth inhibition and regression, achieving up to an 80% regression rate at 100 mg/kg thrice daily, and a TGI of 85% at 50 mg/kg twice daily.