Danusertib

Danusertib is a potent inhibitor of Aurora kinases and Abl (including T315I mutation resistant to approved agents in CML).
 
The Aurora kinases are serine/threonine protein kinases that are essential for proliferating cells and have been identified as key regulators of different steps in mitosis and meiosis, ranging from the formation of the mitotic spindle to cytokinesis. Inhibition of Aurora kinases stops cells from dividing, induces endoreduplication, polyploidy and apoptosis leading to profound antitumour effects in multiple tumour cell type.
 
Danusertib is being tested in different clinical settings, administered iv as single agent or in combination. Pharmacological inhibition of target was demonstrated in clinic, with no major off-target toxicities.
 
Activity was observed in hematological tumors (CML, ALL with T315I mutation) and solid tumors (ovarian, NSCLC). Good ADME properties were observed in man. Main clinical toxicity is hematopoietic (neutropenia), consistent with the mechanism of action.
 
Phase I and phase II trials evaluating Danusertib as single agent or in combination are ongoing for solid tumors and hematological malignancies.

Selected References
  • Phase II study of danusertib (D) in advanced/metastatic breast and ovarian cancers (BC, OC). J Clin Oncol 2010; 28:15s, (Abs 5014).
  • Phase II study of danusertib (D) in advanced/metastatic colorectal and pancreatic cancers (CRC, PC). J Clin Oncol 2010;28, (Abs e13558).
  • Randomized phase II study of danusertib (D) in second-line metastatic castration-resistant prostate cancer (CRPC). J Clin Oncol 2011;29: (Abs 4628).
  • Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors, Journal of Clinical Oncology 2009,27:30(5094-5101)
  • A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors., Clin Cancer Res.(2009) 15(21):6694-701
  • Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358, Cancer Research (2007) 67 (17):7987-90.
  • PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer, Mol Cancer Ther. 2007 6 (12):3158-68
  • 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem. 2006 Nov 30;49(24):7247-51.