Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments

Abstract

As a catalytic subunit of the positive transcription elongation factor b (P-TEFb), cyclin-dependent kinase 9 (CDK9) has been demonstrated to contribute to carcinogenesis. This review focuses on the development of selective CDK9 inhibitors and proteolysis-targeting chimera (PROTAC) degraders. Twenty selective CDK9 inhibitors and degraders are introduced along with their structures, IC50 values, in vitro and in vivo experiments, mechanisms underlying their inhibitory effects, and combination regimens. NVP-2, MC180295, fadraciclib, KB-0742, LZT-106, and 21e have been developed mainly for treating solid tumors, and most of them work only on certain genotypes of solid tumors. Only VIP152 has been proven to benefit the patients with advanced high-grade lymphoma (HGL) and solid tumors in clinical trials. Continued efforts to explore the molecular mechanisms underlying the inhibitory effects, and to identify suitable tumor genotypes and combination treatment strategies, are crucial to demonstrate the efficacy of selective CDK9 inhibitors and degraders in tumor therapy.

Selective inhibition of CDK9 in triple negative breast cancer

“…We also found no effect on neutrophil numbers in the spleen, indicating the neutrophil reservoir was not depleted. This observation is important because neutropenia is a side effect of CDK9 inhibitors, including the only one (VIP152) to show clinical benefit to date [ 47 , 48 ]. Using explants of non-malignant human breast tissues cultured ex vivo, we show that even at doses in the micromolar range, CDDD11-8 had no significant effect on tissue histology or the proliferative index of breast epithelial cells.…”

Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications

“…60,74 However, adverse reactions are commonly seen in clinical trials (NCT02161419). 75 Subsequent advancements led to the development of second-generation pyrimidine-based CDK inhibitors such as 4, AZD5438 (19), and Cpd37d (20). Compounds 4 and 20 have expansive inhibitory spectra: on one hand, 4 targeting CDK1, 2, 5, 7, 9, JAK2, and FLT3; 76 on the other hand, 20 can activate multiple pathways involving PARP and caspase 3 in addition to CDK1, 2, 4, 8, and 9 inhibitions, ultimately inducing apoptosis.…”

“…The C-terminal region primarily constitute 7 α-helices (αD-J) and 4 β-strands (β6–9), housing the catalytic loop, T-loop, and the DFG motif which coordinates with Mg 2+ (Figure A,B). Notably, the T-loop contains Thr186, which is crucial for CDK9 activation . In the absence of cyclin T1, Thr186 occupies the catalytic cleft, preventing ATP binding .…”

“…Many CDK9 inhibitors influence disease progression by downregulating MCL-1. Compounds like LCD000067 ( 7 ), AZD4573 ( 8 ), and 3 reduce Ser2RNAPolII phosphorylation to downregulate MCL-1, while inhibitors like LZT-106 ( 9 ) and AT7519 ( 10 ) modulate the GSK-3β pathway to decrease MCL-1 expression. , MYC, another proto-oncogene regulated by CDK9, undergoes tightly controlled expression in normal cells. However, altered MYC expression is observed in approximately 70% of malignancies, involving mechanisms such as gene amplification, chromosomal translocation, retroviral promoter insertion, enhancer activation, protein degradation, and gene mutations .…”

“…Notably, the T-loop contains Thr186, which is crucial for CDK9 activation. 19 In the absence of cyclin T1, Thr186 occupies the catalytic cleft, preventing ATP binding. 20 Residues in the catalytic loop are highly conserved across CDKs, and they share similar catalytic mechanism that transforms the hydroxyl group of serine or threonine residues on the substrate into a nucleophilic moiety that is capable of attacking the γ-phosphate of ATP (Figure 2C,D).…”