CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas

Abstract

Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.

Targeting CDK9 for Anti-Cancer Therapeutics

“…Unlike many CDKs, the activation of CDK9 is not regulated in a cell-cycle dependent manner but by its association with its cyclin partners to form a heterodimeric complex Positive-Transcription Elongation Factor-b (P-TEFb). Even though Cyclin T1 is the primary cyclin partner of CDK9, minor partners like Cyclins T2a and T2b can also activate CDK9 [ 1 , 32 , 33 ]. In fact, in HeLa cells, the shRNA mediated down-regulation of Cyclin T1 led to the down-regulation of 631 genes, as compared to just 292 genes down-regulated upon the knock-down of Cyclin T2 (both Cyclin T2a and Cyclin T2b) [ 33 ] ( Figure 2 B).…”

“…CDK9 expression had been implicated in the prognosis and resistance to anti-cancer therapeutics in a large number of cancer types like those of breast, lung, prostate, endometrium, apart from melanoma, osteosarcoma, myeloid leukemia, soft tissue sarcomas etc. [ 1 , 88 , 89 , 90 , 91 , 92 ]. We will briefly explain some of these cancer entities here.…”

“…Cassandri et al, in their review article, had listed a number of natural CDK targeting compounds like Indirubins, isolated from several indigo producing plants. A couple of synthetic derivatives of Indirubins like 6-bromoindirubin and 6-bromoindirubin-3′-monooxime were also reported [ 1 ]. Another natural compound Rohitukine, with anti-inflammatory and anti-immunomodulatory properties, derived from the Dysoxylum binectariferum plant, served as the basis for one of the earliest pan-CDK inhibitor Flavopiridol [ 117 ].…”

“…Eventually, it was found to be most effective against CDK9 [ 121 ]. Flavopiridol is an ATP-competitive inhibitor, which showed promising in vitro activity against a number of cancer entities, but demonstrated only limited in vivo activity, except in hematologic cancers like MCL and CLL, resulting in the cessation of its further development [ 1 , 122 ]. Presently, only three trials, involving Flavopiridol, are active, against AML, advanced solid tumors and Myelodysplastic Syndromes (MDS).…”

“…to attain their kinase activity. Presently, this family comprises of 21 members, further classified into three sub-types, broadly based on their regulatory functions: (1) regulators of the cell-cycle-CDKs 1, 2, 4 and 6; (2) regulators of transcription- CDKs 7,8,9,12,13 and 19; (3) regulators of diverse or as yet undefined functions- CDKs 5,10,11,14,15,16,17,18 and 20 [1][2][3]. At present, 29 cyclins have been identified in humans.…”