CDK7 inhibitors as anticancer drugs

Abstract

Cyclin-dependent kinase 7 (CDK7), along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs progression through the cell cycle via T-loop phosphorylation of cell cycle CDKs. CAK is also a component of the general transcription factor, TFIIH. CDK7-mediated phosphorylation of RNA polymerase II (Pol II) at active gene promoters permits transcription. Cell cycle dysregulation is an established hallmark of cancer, and aberrant control of transcriptional processes, through diverse mechanisms, is also common in many cancers. Furthermore, CDK7 levels are elevated in a number of cancer types and are associated with clinical outcomes, suggestive of greater dependence on CDK7 activity, compared with normal tissues. These findings identify CDK7 as a cancer therapeutic target, and several recent publications report selective CDK7 inhibitors (CDK7i) with activity against diverse cancer types. Preclinical studies have shown that CDK7i cause cell cycle arrest, apoptosis and repression of transcription, particularly of super-enhancer-associated genes in cancer, and have demonstrated their potential for overcoming resistance to cancer treatments. Moreover, combinations of CDK7i with other targeted cancer therapies, including BET inhibitors, BCL2 inhibitors and hormone therapies, have shown efficacy in model systems. Four CDK7i, ICEC0942 (CT7001), SY-1365, SY-5609 and LY3405105, have now progressed to Phase I/II clinical trials. Here we describe the work that has led to the development of selective CDK7i, the current status of the most advanced clinical candidates, and discuss their potential importance as cancer therapeutics, both as monotherapies and in combination settings. ClinicalTrials.gov Identifiers: NCT03363893; NCT03134638; NCT04247126; NCT03770494.

Targeting Mutated p53 Dependency in Triple-Negative Breast Cancer Cells Through CDK7 Inhibition

“…Its expression frequently increases in many cancers and is important for tumor development ( 10 , 12 ). A number of CDK7 inhibitors are considered to be potential drug candidates for cancer therapy because they are highly cytotoxic to tumor cells only ( 13 , 21 , 22 ). One main concern regarding the application of CDK7 inhibitors in cancer therapy is the variable sensitivity of different cancer types to CDK7 inhibition, which has been found in preclinical studies.…”

Super-enhancer in prostate cancer: transcriptional disorders and therapeutic targets

“…Rasool et al demonstrated that THZ1 attenuated the AR-signaling and maintained efficacy in CRPC and enzalutamide-resistant PCa cells 47 . Also, CDK7 selective inhibitors have been developed, such as SY1365 and CT7001, and evaluated in clinical trials in other advanced solid tumors 100,101 . ERG overexpression is observed in a large group of primary PCa and CRPC.…”

G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181

“…Furthermore, it has recently been reported that four CDK7 inhibitors (ICEC0942, SY-1365, SY-5609, and LY3405105), which were developed to improve the poor bioavailability and insufficient permeability of BS-181, have progressed to phase I/II clinical trials for evaluating their antitumor efficacy [ 43 ]. Although only ICEC0942 among these four CDK inhibitors is a BS-181 analog that has been developed to retain the CDK7 selectivity of BS-181 [ 44 ], and is thus highly likely to induce extrinsic apoptosis through TRAIL/DR5 upregulation in tumor cells, the contributions of these CDK7 inhibitors to the extrinsic TRAIL/DR5-dependent apoptosis induction in tumor cells and their synergistic cytotoxic effect exerted by cotreatment with rTRAIL remain to be elucidated.…”