Abstract P1-10-05: ICEC0942, a new oral selective inhibitor of the cell cycle and transcriptional regulator CDK7 for the treatment of estrogen receptor positive and negative breast cancer
Authors: Ali S , Patel H , Periyasamy M , Sava G , Bondke A , Slafer BW , Kroll SHB , Barbazanges M , Starkey R , Ottaviani S , Harrod A , Aboagye EO , Buluwela L , Fuchter MJ , Barrett AGM , Coombes RC 
Published: February 2018

Abstract
CDK7 is remarkable as a key regulator of both cell cycle progression and gene expression. CDK7 promotes cell cycle progression by phosphorylating cell cycle CDKs in the T-loop, thus stimulating their activities. Additionally, 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). Screening of more than one thousand analogues has allowed development of a clinical candidate CDK7 inhibitor, named ICEC0942. ICEC0942 selectively inhibits CDK7 with an IC50 of 40nM. In vitro analyses reveal that ICEC0942 inhibits hormone receptor positive and triple-negative 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 using several cancer cell lines, the drug shows substantial anti-tumor 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.
Extensive ADMET and PK/PD studies confirm the suitability of ICEC0942 as a cancer drug and have shown that ICEC0942 is orally bioavailable. Moreover, xenograft tumor studies have allowed definition of surrogate biomarkers of tumor response.
Taken together, our findings confirm CDK7 as an important drug target for ER-positive and -negative breast cancer and identify ICEC0942 as a prototype drug with utility as a single agent or in the combination setting. Our findings also point to the potential value of CDK7 inhibition by ICEC0942 in other cancer types that have characteristics of transcription factor addiction and/or cell cycle deregulation.
Development of ICEC0942 was made possible through funding by EPSRC, Cancer Research UK and Cancer Research Technologies.
Citation Format: Ali S, Patel H, Periyasamy M, Sava G, Bondke A, Slafer BW, Kroll SHB, Barbazanges M, Starkey R, Ottaviani S, Harrod A, Aboagye EO, Buluwela L, Fuchter MJ, Barrett AGM, Coombes RC. ICEC0942, a new oral selective inhibitor of the cell cycle and transcriptional regulator CDK7 for the treatment of estrogen receptor positive and negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-05.