CDK9 inhibitors in cancer research

Abstract

Cyclin dependent kinase 9 (CDK9) plays an essential role in regulating transcriptional elongation. Aberrations in CDK9 activity have been observed in various cancers, which make CDK9 an attractive therapeutic target for cancers. This led to an intensive development of small-molecule CDK9 inhibitors or new emerging strategies, such as proteolysis targeting chimeras (PROTACs). Here, we review the CDK9 modulators in cancer not only for research purposes, but also for therapeutic applications.

Fig. 1. Structure of CDK9/cyclin T (PDB: 3BLR).

Fig. 2. The development of CDK9 inhibitors with flavonoid cores.

Fig. 3. (A) The crystal structure of flavopiridol (green) and CDK9 (pink, PDB: 3BLR). (B) The predicted binding mode of compound IIIM-290 (green) and CDK9 (pink, PDB: 3BLR). (C) The predicted binding mode of compound 51 (green) and CDK9 (pink, PDB: 3BLR). (D) The predicted binding mode of compound 13c (green) and CDK9 (pink, PDB: 3BLR). (E) The predicted binding mode of compound LZT-106 (green) and CDK9 (pink, PDB: 3BLR). The hydrogen bonds are depicted by red dotted lines.

Fig. 4. (A) The development of CDK9 inhibitors with aminopyrimidine cores. (B) The crystal structure of 12u (green) bound to CDK9/cyclin T1 (pink, PDB: 4BCG).

Fig. 5. The development of CDK9 inhibitors with pyridine (or triazine) cores.

Fig. 6. (A) The predicted binding mode of AZ5576 (green) and CDK9 (pink, PDB: 4BCF). (B) The crystal structure of AZD4573 (green) bound to CDK9 (pink, PDB: 6Z45). (C) The predicted binding mode of JSH-150 (green) and CDK9 (pink, PDB: 4BCG). (D) The predicted binding mode of FIT-039 (green) and CDK9 (pink, PDB: 3BLQ). The hydrogen bonds are depicted by red dotted lines.

Fig. 7. The development of CDK9 inhibitors with purine cores.

Fig. 8. (A) The development of CDK9 inhibitors with pyrazolo[1,5-a]pyrimidine cores. (B) The predicted binding mode of KB-0742 (green) and CDK9 (pink, PDB: 3MY1). The hydrogen bonds are depicted by red dotted lines.

Fig. 9. (A) The development of CDK9 inhibitors with pyrazole cores. (B) The crystal structure of CAN508 (green) bound to CDK9 (pink, PDB: 3TN8). The hydrogen bonds are depicted by red dotted lines.

Fig. 10. The development of CDK9 inhibitors with aminothiazole cores.

Fig. 11. (A) The development of CDK9 inhibitors with azaindole cores or nitrogen-containing heterocycles. (B) The crystal structure of compound 6 (green) with CDK9 (pink, PDB: 7NWK). The hydrogen bonds are depicted by red dotted lines.

Fig. 12. (A) The development of CDK9 inhibitors with pyrrolo[2,3-d]pyrimidin cores. (B) The predicted binding mode of compound 6e (green) and CDK9 (pink, PDB: 4BCF). (C) The predicted binding mode of compound 21e (green) and CDK9 (pink, PDB: 4BCF). The hydrogen bonds are depicted by red dotted lines.

Fig. 13. Chemical structure of designing PROTAC degrader 3 based on compound 1.

Fig. 14. Chemical structure of designing PROTAC 11c based on wogonin.

Fig. 15. Chemical structure of designing PROTAC THAL-SNS-032 based on SNS-032.

Fig. 16. Chemical structure of designing PROTAC F3 based on compound FN-1501.

Fig. 17. Chemical structure of designing PROTAC B03 based on BAY-1143572.

Fig. 18. Chemical structure of designing PROTAC 2.

Fig. 19. Chemical structure of designing degrader 45.

Fig. 20. (A) The main amino acid residues of CDK9 (PDB: 3BLR) that formed interactions with the inhibitors. The hydrophobicity ranges its intensity from 3.00 (maximum hydrophobic zones) to −3.00 (minimum hydrophobic zones). The minimum intensity areas are the blue shaded regions and the maximum intensity areas are denoted with dull brownish color. (B) Atoms of inhibitors participating in hydrogen bonds with the hinge region of CDK9 are shown in purple shadow.