Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update

Abstract

Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. In particular, CDK9 promotes RNA polymerase II pause/release, a rate-limiting step in normal transcriptional regulation that is frequently dysregulated in cancers. Emerging evidence indicates that selective CDK9 inhibition or degradation may provide a therapeutic benefit against certain cancers. Indeed, the development of CDK9 modulators (inhibitors and degraders) has attracted great attention, with several molecules currently under clinical development. This review provides an overview of recent advances in CDK9 modulators in general, with special emphasis on compounds under clinical evaluation and new emerging strategies, such as proteolysis targeting chimeras (PROTACs).

Targeting CDK9 for the Treatment of Glioblastoma

“…Several inhibitors have been or are currently being tested in clinical trials for the treatment of various cancers [ 22 ] and are listed in Table 1 and summarized here. The majority of these inhibitors are potent against CDK9, with 50% inhibitory concentration (IC 50 ) values in the nanomolar (nM) range [ 78 ]. However, they are also nonselective, and target other CDKs (often at IC 50 values in the nM range as well) since the ATP-binding pocket is conserved in the entire CDK family [ 32 , 78 ].…”

“…The majority of these inhibitors are potent against CDK9, with 50% inhibitory concentration (IC 50 ) values in the nanomolar (nM) range [ 78 ]. However, they are also nonselective, and target other CDKs (often at IC 50 values in the nM range as well) since the ATP-binding pocket is conserved in the entire CDK family [ 32 , 78 ]. Moreover, inhibitors may target kinases other than CDKs, resulting in some adverse effects [ 78 ].…”

“…However, they are also nonselective, and target other CDKs (often at IC 50 values in the nM range as well) since the ATP-binding pocket is conserved in the entire CDK family [ 32 , 78 ]. Moreover, inhibitors may target kinases other than CDKs, resulting in some adverse effects [ 78 ]. This has limited the clinical utility of some inhibitors, resulting in termination from clinical trials.…”

“…This has limited the clinical utility of some inhibitors, resulting in termination from clinical trials. For example, ZK-304709, an inhibitor of CDKs 1, 2, 4, 7, and 9 as well as Vascular Endothelial Growth Factor Receptor (VEGFR)-1, 2, and 3, Platelet-derived Growth Factor Receptor (PDGFR)-β, and FMS-like Tyrosine Kinase (FLT)-3 [ 78 , 79 ], was prematurely terminated in a phase I study for patients with advanced solid tumors due to severe adverse effects of nausea and vomiting [ 80 ]. The investigation of SNS-032, which primarily targets CDKs 2, 7, and 9 [ 81 ], in a phase I study for patients with metastatic refractory solid tumors was similarly discontinued, in part because of toxicity issues, since all patients reported side effects, such as fatigue, nausea, diarrhea, and abdominal pain [ 81 ].…”

“…Some inhibitors have shown encouraging results in some of their clinical trials (while still demonstrating adverse outcomes in other trials) and have garnered orphan drug status by the FDA. One such drug is flavopiridol/alvocidib, which inhibits CDKs 1, 2, 4, 5, 6, 7, and 9 and Glycogen Synthase Kinase (GSK)-3β, though it is most potent against CDK9 with an IC 50 of 3nM [ 78 ]. In 1994, flavopiridol became the first CDK inhibitor to enter clinical trials [ 22 ] and has now become the most frequently investigated CDK9 inhibitor in clinical trials [ 32 ].…”