simurosertib (TAK-931)

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.

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.

Simurosertib (TAK-931) significantly suppressed the proliferation of LUAD cells by inhibiting cell division cycle 7-mediated MCM2 phosphorylation...Moreover, analysis of the epigenetic regulation of MCM2 showed that miR-139-3p, miR-378a-5p, and miR-2110 modulated MCM2 expression in LUAD cells. In patients with LUAD, understanding the role of these miRNAs may improve prognoses.

The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors.

(Trial registration number ClinicalTrials.gov NCT03708211. Registration date October 12, 2018).

This is the first study to display the potential of utilizing the combined inhibition of DDK and WEE1 for the treatment of cancer. We believe this will offer a potential therapeutic strategy for the treatment of Ewing sarcoma as well as other tumor types that display sensitivity to DDK inhibitors.

At the geometric mean maximum TAK-931 plasma concentrations after administration of 50 mg, an HR change of 3.40 beats per minute (90%CI, 1.86-4.80) was predicted. Change in QTcF of -3.41 milliseconds (90%CI, -5.77 to -1.17) and QTcP of -2.02 milliseconds (90%CI, -4.15 to 0.0679) were estimated, indicating there was no effect of TAK-931 on the QT intervals at a recommended phase 2 dose of 50 mg once daily for 14 days in a 21-day cycle.

The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931.

P1, N=20, Completed, Millennium Pharmaceuticals, Inc. | Recruiting --> Completed | N=44 --> 20