NMS-1286937

Nerviano Medical Sciences is developing NMS-1286937, a novel, orally-available PLK1-specific inhibitor.

Polo-like kinase 1 (PLK1) is a serine / threonine protein kinase considered to be the master player of cell cycle regulation during mitosis.
PLK1 is over-expressed in a variety of human tumors and its over-expression often correlates with poor prognosis. Depletion or inhibition of the kinase activity of PLK1 is sufficient to induce cell cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models.

Preclinical evaluation has shown high potency of the compound in proliferation assays, displaying low nanomolar activity on a large number of cell lines, representative of both solid and hematological tumors. NMS-1286937 potently causes a mitotic cell cycle arrest followed by apoptosis in cancer cell lines and it inhibits xenograft tumor growth with demonstrated PLK1-related mechanism of action, after oral administration.
NMS-1286937 also shows potential for combination with approved cytotoxic drugs in various clinical settings, causing tumor regression in xenograft models.

Currently a phase I trial evaluating NMS-1286937 for the treatment of solid tumors is ongoing.

 Selected references

  • Pyrazoloquinazolines: From an unselective hit to a potent Plk-1 specific inhibitor, American Association for Cancer Research Annual Meeting2009,100th:April 19(Abs 1812)
  • Oral presentation, Protein Kinases - Informa's Seventh Annual Congress (Part II), Berlin, Germany, 10-12 March 2008
  • Antitumoral activity of pyrazoloquinazoline derivatives as potent oral Plk-1 specific inhibitors, EORTC-NCI-AACR International Congress2008,20th:October 23(Abs 434)
  • Characterization of small molecular weight inhibitors of Polo-like kinase-1, Proceedings of the American Association for Cancer Research2006,47(Abs 1534)
  • Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors, J Med Chem. 2010 May 13;53(9):3532-51
  • A Phase I Dose Escalation Study of NMS-1286937 Administered to Adult Patients With Advanced/Metastatic Solid Tumors, NCT01014429, www.clinicaltrial.gov
  • NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor, Bioorg Med Chem Lett. 2011 May 15;21(10):2969-74