We show that CDC7 inhibitor simurosertib phenocopies VK1727, while Bcl-2 inhibitor venetoclax shows a synergistic effect with VK1727 for inhibition of EBV+ epithelial cancer cell proliferation and survival. We identify cell cycle-dependent kinase CDC7 and the stem cell transcription factor POU2F1 as EBNA1-bound and regulated genes important for EBV epithelial cancer proliferation. These findings not only decipher the molecular mechanism by which VK1727 blocks cell cycle progression and inhibits cell proliferation but also provide two new cellular gene targets and pathways for therapeutic intervention in EBV+ epithelial cancers.

TAK-931 treated prostate cancer cells exhibit an abnormal cell cycle profile, suggesting that CDC7 inhibition induces replication stress and promotes apoptosis. Collectively, our findings demonstrate that CDC7 is a regulator of tumor progression in prostate cancer and represents new therapeutic target in advanced prostate cancer.

P1, N=66, Terminated, Schrödinger, Inc. | N=50 --> 66 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> Aug 2025; Company decision

P1/2, N=90, Recruiting, Lin BioScience, Inc | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

P1/2, N=90, Recruiting, Lin BioScience, Inc | N=60 --> 90

CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

The docking scores measured for PYRA-1 and PYRA-2 with CDC7 kinase complexes are -5.421 and -5.884 kcal/mol, respectively. The MD simulations show that PYRA-2 is a more potential inhibitor than PYRA-1 against CDC7 kinase.

P1, N=50, Recruiting, Schrödinger, Inc.

Finally, the combination of TAK-931 and immune checkpoint inhibitors profoundly enhance antiproliferative activities. These findings suggest that TAK-931 has therapeutic antitumor properties and improved clinical benefits in combination with conventional immunotherapy.

One possible reason for the failure might be due to the dose-limiting toxicities, and some of the observed toxicities were thought to be not related to CDC7 inhibition, suggesting it should be important to identify novel chemical scaffolds to eliminate unwanted toxicities. Another important factor is the patient stratification that would enable greater response, and the identification of such predictive biomarkers should be the key to success for the development of CDC7 inhibitors.

Our data show remarkable dose-dependent in vivo activity of SGR-2921 in AML PDX models, including in those representing difficult-to-treat disease. Direct inhibition of CDC7 by SGR-2921 in AML blasts was demonstrated by a dose-dependent reduction of phosphorylated MCM2. Together, these data demonstrate that SGR-2921-mediated CDC7 inhibition is an attractive novel treatment opportunity in AML, with potential utility in patients with high risk mutations and relapsed and refractory AML.

The study primary objectives are to evaluate the safety and tolerability of SGR-2921 as monotherapy and identify RP2D including MTD. Secondary objectives include evaluating the pharmacokinetics (PK) of SGR-2921 and investigating preliminary antitumor activity (composite complete remission rate, objective response rate, duration of response, etc.).