Mitosis Regulation



A highly selective inhibitor of a mitotic pathway enzyme polo-like kinase 1

Polo-like kinase 1 (PLK1) is a serine/threonine kinase with a central role in cell division, or mitosis, and is an important regulator of the DNA damage checkpoint. Removal of Plk1 gene leads to embryonic lethality in mice signifying the functional utility of this kinase. Plk1 is an oncogene and when overexpressed, causes cellular transformation, overrides the DNA damage checkpoint, contributes to checkpoint adaptation, supports invasion through the extracellular matrix and paves the way for aneuploidy. Development of an inhibitor to PLK1 to control aberrant tumor growth is therefore a reasonable proposition.

CYC140 is a novel, small molecule, selective, ATP-competitive, PLK1 inhibitor of low nanomolar potency. It shows selective target inhibition, impressive efficacy and cures human tumor xenografts at non-toxic doses. Both oral and parenteral forms were found to be extremely potent in xenograft models.

Preclinical and translational investigation revealed that:

  • various AML and ALL cell lines were highly sensitive to CYC140 treatment with appropriate target engagement
  • multiple esophageal cancer (OEC) cell lines were sensitive to short-pulse dosing of CYC140
  • other cancers in which PLK1 is overexpressed and correlates with poor prognosis include breast, colon, head and neck, melanoma, NHL, NSCLC, ovarian, pancreatic, prostate and thyroid.

Cyclacel will develop CYC140 in acute leukemias first, and later in solid tumors once the proof-of-concept is achieved in human and the safety-tolerability is established. Following IND-enabling studies, the first-in-human (FIH) trial is ready to enroll advanced leukemia patients at the M.D. Anderson Cancer Center (MDACC). Recently, MDACC and Cyclacel established a multi-year collaborative agreement, and CYC140 will be investigated by experienced and world-renowned clinicians at the MDACC.

Learn more about CYC140 (PDF)

Research & Development