NMS-1116354

NMS-1116354 is an inhibitor of the protein Cell division cycle 7 (Cdc7).

Cdc7 is a serine/threonine kinase that promotes DNA replication origin firing by phosphorylating the MCM helicase complex, thus leading to the DNA unwinding.

Cdc7 inhibition causes tumor cells to enter apoptosis in a p53 independent manner and without activating a DNA damage response, while simply and reversibly arresting cell cycle progression in normal cells.

Furthermore, Cdc7 is a downstream target of the S-phase replication checkpoint and it is therefore not only an essential cell cycle regulator but also important for genomic integrity in response to DNA damage. Inhibiting Cdc7 in combination with chemotherapy may enhance tumor cell death by preventing these cells from recovering from DNA damage.

NMS-1116354 is a small molecule Cdc7 oral inhibitor able to induce tumor regression as single agent as well as in combination in preclinical cancer models, in particular in breast cancer and in acute leukemia.

Phase I trials evaluating NMS-1116354 for solid tumors and hematological malignancies are ongoing.

Selected references

  • A Phase I Dose-Escalation Study of NMS-1116354 in Adult Patients With Advanced Solid Tumors, NCT01016327, www.clinicaltrial.gov
  • A Phase I Dose-Escalation Study of NMS-1116354 in Adult Patients With Advanced/Metastatic Solid Tumors, NCT01092052, www.clinicaltrial.gov
  • "NMS-1116354: More than an inhibitor of Cdc 7 kinase in S-phase", American Association for Cancer Research Annual Meeting 2010,101st:April 18 (Abs DD01-01)
  • "Activity of the Cdc7 inhibitor NMS-1116354 as single agent and in combination in breast cancer models", 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. Berlin, Germany. 2010.
  • "Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding". Journal of Medicinal Chemistry Oct 28;53(20):7296-315, 2010.
  • "Targeting Cdc7 kinase: a new approach for cancer therapy". Clinical Cancer Research Sep 15;16(18):4503-8, 2010.
  • "Cell division cycle 7 kinase Inhibitors: 1h-pyrrolo(2,3-b)pyridines, synthesis and Structure-Activity Relationships". Journal of Medicinal Chemistry 23;52(14):4380-90,2009
  • "First Cdc7 Kinase Inhibitors: Pyrrolopyridinones as Potent and Orally Active Antitumor Agents. 2. Lead Finding". Journal of Medicinal Chemistry 22;52(2):293-307, 2009.
  • "A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity". Nature Chemical Biology 4(6):357-65, 2008.
  • "Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships". Journal of Medicinal Chemistry 14; 51(3): 487-501, 2008
  • "Cdc7 is an active kinase in human cancer cells undergoing replication stress". Journal of Biological Chemistry 5; 282 (1): 208-15, 2007.
  • "Identification of Mcm2 phosphorylation sites by S-phase regulating kinases". The Journal of Biological Chemistry, 14; 281 (15): 10281-90, 2006. .
  • "Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells". Cancer Research, 64: 7110-7116, 2004.