Data from: Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer

Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of
uncontrolled proliferation and increased survival. As a result, over the
last two decades substantial efforts have been directed towards
identification and development of pharmaceutical CDK inhibitors. Insights
into the biological consequences of CDK inhibition in specific tumor types
have led to the successful development of CDK4/6 inhibitors as treatments
for certain types of breast cancer. More recently, the development of a
new generation of pharmaceutical inhibitors of CDK enzymes that regulate
the transcription of key oncogenic and pro-survival proteins, including
CDK2 and CDK9, have entered clinical development. Here, we provide the
first disclosure of the chemical structure of fadraciclib (CYC065), a CDK
inhibitor and clinical candidate designed by further optimization from the
aminopurine scaffold of seliciclib. We describe its synthesis and
mechanistic characterization. Fadraciclib exhibits improved potency and
selectivity for CDK2 and CDK9 compared to seliciclib, and also displays
high selectivity across the kinome. We show that the mechanism of action
of fadraciclib is consistent with potent inhibition of CDK9-mediated
transcription, decreasing levels of RNA polymerase II C-terminal domain
serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1
(MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells.
This cellular potency and mechanism of action translate to promising
anti-cancer activity in human leukemia mouse xenograft models. Studies of
leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene
status and the level of B-cell lymphoma 2 (BCL2) family proteins as
potential markers for selection of patients with greater sensitivity to
CYC605. We show that the combination of fadraciclib with BCL2 inhibitors,
including venetoclax, is synergistic in leukemic cell models, as predicted
from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways.
Fadraciclib preclinical pharmacology data support its therapeutic
potential in CDK9- or CDK2-dependent cancers and as a rational combination
with BCL2 inhibitors in hematological malignancies. Fadraciclib is
currently in Phase 1 clinical studies in patients with advanced solid
tumors (NCT02552953) and also in combination with venetoclax in patients
with relapsed or refractory chronic lymphocytic leukemia (CLL)
(NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or
myelodysplastic syndrome (MDS) (NCT04017546)