ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment

Abstract

Recent reports indicate that some cancer types are especially sensitive to transcription inhibition, suggesting that targeting the transcriptional machinery provides new approaches to cancer treatment. Cyclin-dependent kinase (CDK)7 is necessary for transcription, and acts by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (PolII) to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor (ER)-α. Here we describe a new, orally bioavailable CDK7 inhibitor, ICEC0942. It selectively inhibits CDK7, with an IC of 40 nmol/L; IC values for CDK1, CDK2, CDK5, and CDK9 were 45-, 15-, 230-, and 30-fold higher. studies show that a wide range of cancer types are sensitive to CDK7 inhibition with GI values ranging between 0.2 and 0.3 μmol/L. In xenografts of both breast and colorectal cancers, the drug has substantial antitumor effects. In addition, combination therapy with tamoxifen showed complete growth arrest of ER-positive tumor xenografts. Our findings reveal that CDK7 inhibition provides a new approach, especially for ER-positive breast cancer and identify ICEC0942 as a prototype drug with potential utility as a single agent or in combination with hormone therapies for breast cancer. ICEC0942 may also be effective in other cancers that display characteristics of transcription factor addiction, such as acute leukaemia and small-cell lung cancer. .

Transcriptional control of DNA repair networks by CDK7 regulates sensitivity to radiation in Myc-driven Medulloblastoma

“…As a whole CDK7 inactivation dismantles two mechanisms needed for medulloblastoma proliferation and survival. These data are particularly relevant given the recent development of clinical grade CDK7 inhibitors (Hu et al, 2019a;Hu et al, 2019b;Patel et al, 2018). CDK7 inhibition with SY-5609 has already entered clinical trials (NCT04247126).…”

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

“…ICEC0942 is an orally bioavailable CDK7 inhibitor also being evaluated in preclinical studies (155). Whereas, THZ1 has a covalent mechanism of action and may interact with other kinases, ICE0942 has a non-covalent mechanism of action, which could possibly limit side effects (154,155). Oral administration of ICE0942 in mice showed favorable safety with no adverse effects on liver or kidney function (155).…”

ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942

“…S1). THZ1 inhibits CDK7 by covalently targeting a cysteine residue (C312), which lies outside the ATP-binding domain [10], whereas ICEC0942 is an ATP-competitive CDK7i [16]. It has been shown that mutation of C312 to serine (C312S), is sufficient to prevent THZ1 from covalently binding to CDK7 and from inhibiting CDK7 activity [10], therefore it was possible that a mutation of C312 could be responsible for the THZ1-resistance and continued sensitivity to ICEC0942 in MCF7-THZ1 R .…”

“…Whole cell lysates were prepared in RIPA buffer (Sigma-Aldrich), supplemented with protease and phosphatase inhibitors (Roche, UK), and immunoblotting was carried out as previously described [16]. Antibodies used were; Pol II (ab26721), Pol II-phosphoserine-2 (ab5095), Pol IIphosphoserine-5 (ab5131), Pol II-phosphoserine-7 (ab126537) and β actin (ab6276), purchased from Abcam (Cambridge, UK), and ABCB1 (D3H1Q) and ABCG2 (4477), purchased from Cell Signaling Technology (Danvers, MA, USA).…”

“…Recently, these findings have become embodied in a wider framework known as "Transcription addiction in cancer" [14], a concept that supports CDK7 as a potentially valuable cancer drug target, as it plays key roles in both the regulation of transcription and the cell cycle. We reported the first selective CDK7 inhibitor, BS-181, as an ATP-competitive CDK7 inhibitor [15], which served as a lead compound for development of the oral clinical candidate ICEC0942 [16], which is currently undergoing Phase I trial for advanced solid malignancies, under the name CT7001. A second, covalent CDK7 inhibitor, THZ1 [10], has been independently developed and a THZ1-derived compound SY-1365 [17] is also undergoing Phase I trial for advanced solid malignancies.…”