PEP07: A novel, brain penetrant oral Chk1 inhibitor for the treatment of AML and MCL

DDR Inhibitor Summit, Boston, MA, January 2023.

ABSTRACT: Chk1 is a key modulator of the cell division cycle and DNA damage response (DDR) signaling.  Inhibition of Chk1, in conjunction with additional genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treat cancer.

Acute myeloid leukemia (AML) is characterized by a deranged DDR pathway and high Chk1 expression that is associated with poor patient outcomes. Mantle cell lymphoma (MCL) is a rare and aggressive form of Non-Hodgkin lymphoma with the genetic hallmark of a chromosomal translocation leading to the over expression of cyclin D1.  Since Chk1 regulates cdk1/cyclin activity, Chk1 inhibitors have been proposed as a novel therapeutic approach in this cancer.

Here, we present PEP07, an orally available brain penetrant selective Chk1 inhibitor that is entering first in human clinical studies in AML and MCL.