ICEC0942, a new oral selective inhibitor of the cell cycle and transcriptional regulator CDK7 for the treatment of breast and other cancers


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Simak Ali1
1Imperial College London

Abstract

Background

CDK7 is remarkable as a key regulator of both cell cycle progression and gene expression. It promotes cell cycle progression by phosphorylating cell cycle CDKs to stimulate their activities. Importantly, phosphorylation of RNA polymerase II (PolII) by CDK7 is required for transcription initiation. Deregulation of cell cycle and transcription processes is common to most cancer types, so CDK7 inhibitors offer considerable promise as cancer therapeutics. We previously reported the identification of the first selective CDK7 inhibitor, BS-181, and demonstrated its ability to inhibit breast cancer cell growth in vitro and in vivo (Ali et al 2009 Cancer Res).

Method

Towards development of a clinical candidate, we undertook synthesis and screening of >1000 analogues using:

  1. in vitro kinase inhibition,
  2. cell-based growth inhibition and target engagement assays
  3. ADMET/PK.

Results

We have identified ICEC0942, which selectively inhibits CDK7 with an IC50 of 40nM. In vitro analyses reveal that ICEC0942 inhibits hormone receptor positive breast cancer cell lines, with GI50 values ranging between 0.2-0.3 μM. Growth inhibition is accompanied by inhibition of CDK7 targets, including CDK1, CDK2 and PolII phosphorylation. In xenograft studies, the drug shows substantial anti-tumour effects, with a notable lack of toxicity at efficacious doses. In the combination setting with tamoxifen, ICEC0942 completely blocks growth of ER-positive tumor xenografts, indicative of potential for co-treatment with hormonal agents. 

Cancer cell line screening and xenograft studies demonstrate potential for ICEC0942 for treating other cancer types, including triple-negative breast, lung and colorectal cancer and leukaemias.

ADMET and PK/PD studies confirm the suitability of ICEC0942 as a cancer drug, including oral bioavailability. 

Conclusion

Our findings confirm CDK7 as an important cancer target and identify ICEC0942 as a prototype drug with utility as a single agent or in the combination setting, results that have led to initiation of a phase I study, as CT7001 (ClinicalTrialsgov: NCT03363893).