CID-078 is an oral macrocyclic cyclin A/B-RxL dual inhibitor. CID-078 binds to the hydrophobic patch region of Cyclin A/B, disrupting protein-protein interactions within the HP-RxL-mediated Cyclin A2/CDK2–E2F1 and Cyclin B1/CDK1–MYT1 complexes, leading to cell cycle arrest and tumor apoptosis. CID-078 selectively kills E2F pathway-driven tumor cells and induces tumor regression in mouse xenograft models. CID-078 is suitable for research on advanced solid tumors, including small cell lung cancer, triple-negative breast cancer, neuroendocrine cancer, and CDK4/6 inhibitor-resistant breast cancer.

CID-078 exhibits antiproliferative activity against 46 small cell lung cancer (SCLC) and 104 non-small cell lung cancer (NSCLC) cell lines, with enhanced activity in cells exhibiting high E2F and G2M pathway scores and/or upregulated cyclin B1 and separase expression. [1]
Treatment with CID-078 for 4–8 days inhibits the proliferation of various solid tumor cell lines, with significantly greater efficacy (lower GI50) in cell lines with RB1 abnormalities; In SCLC, triple-negative breast cancer (TNBC), and NSCLC cell lines, increased sensitivity is associated with high expression of E2F targets and elevated G2/M checkpoint pathway scores. [3]
CID-078 binds to the hydrophobic patch/RxL binding site of the cyclin-CDK complex, blocking the interactions between E2F1-cyclin A-CDK2 and MYT1-cyclin B-CDK1, and induces replicative stress, DNA damage, and mitotic catastrophe in tumor cells with high E2F1 expression. [3]
Treatment with CID-078 for 72 h inhibits the growth of established neuroblastoma cell lines, with GI50 ranges from 0.001 μM (SKNSH) to 10 μM (SY5Y WT, GIMEN, TR14, SKNAS). [4]
Treatment with CID-078 for 72 h significantly sensitizes CDKN2A-inactivated SH-SY5Y neuroblastoma cells; compared to wild-type cells with a GI₅₀ >10 μM, the GI₅₀ values for the C7.3 and C8.10 clones were only 55 nM and 6 nM, respectively. [4]
Treatment with CID-078 for 120 h significantly inhibits the growth of patient-derived neuroblastoma organoid models, with a GI₅₀ range of 0.01–1 μM [4].
Treatment with CID-078 (100 nM) for 24 h induces G2/M phase arrest in neuroblastoma cell lines, with the proportion of G2/M cells increasing by 52% (SY5Y C7.3) to 632% (SKNSH) compared to the DMSO control group [4].
Treatment with CID-078 (0–200 nM) for 24 h activates the spindle assembly checkpoint (phosphorylated BUBR1), induces DNA damage (phosphorylated γH2AX), and upregulates G2/M phase markers (phosphorylated FoxM1) in neuroblastoma cell lines and hTERT-RPE1 healthy control cells.[4]

In TNBC RB1-mutant PDX models and luminal HR+/HER2- PDX models treated with CDK4/6 inhibitors, oral administration of CID-078 (100 mg/kg) twice daily demonstrated potent monotherapy activity. [3]
In xenograft models characterized by RB pathway dysregulation and upregulation of the E2F transcriptional program, oral administration of CID-078 produced dose-dependent tumor growth inhibition and led to tumor regression.[5]