Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy

Abstract

The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.

Fig. 1. Pyrazolopyridine non-kinase drugs and drug candidates.

Fig. 2. Pyrazolopyridine-based anticancer kinase inhibitors.

Fig. 3. Isomers of pyrazolopyridine.

Fig. 4. Optimization of the pyrazolo[3,4-b]pyridine-based CDK8 inhibitor MSC2530818 (26).

Fig. 5. (A) X-ray crystal structure of compound 23 in CDK8 (PDB ID: 5ICP). (B) X-ray crystal structure of compound 26 in CDK8 (PDB ID: 5IDN). The hinge residues are illustrated in red and αC-helix residues in green.

Fig. 6. Optimization of pyrazolo[1,5-a]pyridine-based CSK inhibitor 28 from a pyridazinone lead.

Fig. 7. Molecular docking-based binding pose of compound 28 in the CSK structure (PDB ID: 1BYG). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 8. Identification of pyrazolo[4,3-c]pyridine-based mutant selective EGFR inhibitor 30.

Fig. 9. (A) X-ray crystal structure of compound 29 in EGFR T790M/L858R mutant (PDB ID 5CAS). (B) X-ray crystal structure of compound 30 in EGFR T790M/L858R mutant (PDB ID 5HCZ). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 10. Pyrazolo[4,3-c]pyridin-6-yl urea derivative 32, an ERK inhibitor, developed from SCH772984.

Fig. 11. (A) X-ray crystal structure of benzylurea analog of compound 32 in ERK (PDB ID: 5KE0). (B) Molecular docking-based binding pose of compound 34 in FGFR kinase (PDB ID: 4WUN). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 12. Chemical structures of NVP-BGJ398 and PD173074, and the development of pyrazolo[3,4-b]pyridine-based selective FGFR inhibitor 34 from AZD4547.

Fig. 13. 1-Sulfonyl-pyrazolo[4,3-b]pyridine c-Met inhibitors developed from a 4-azaindole scaffold.

Fig. 14. Molecular docking-based binding pose of glumetinib in c-Met kinase (PDB ID: 2WD1). The hinge residues are illustrated in red and the DFG motif in blue.

Fig. 15. (A) Optimization of compound 39 from compound 38. (B) Molecular docking of compound 39 in ITK (PDB ID: 1SM2). The hinge residues are illustrated in red and DFG motif in blue.

Fig. 16. (A) Optimization of 3,5-disubstituted pyrazolo[3,4-c]pyridine 39 as a potent pan-Pim inhibitor. (B) Chemical structures and K_i values of Frag-1, Frag-2 and Frag-3.

Fig. 17. (A) X-ray crystal structure of compound 40 in Pim-1 kinase (PDB ID: 5DGZ). (B) X-ray crystal structure of Frag-2 in Pim-1 kinase (PDB-ID: 5DHJ). (C) X-ray crystal structure of compound 43 in Pim-1 kinase (PDB ID: 5V82). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 18. Development of N-pyridyl pyrazolo[4,3-c]pyridine 44 as an oral pan-Pim inhibitor.

Fig. 19. Identification of compounds 46 and 47 from compound 45 based on the scaffold hopping strategy.

Fig. 20. (A) Molecular docking-based binding pose of 47 in BRAF V600E (PDB ID: 3OG7). (B) Molecular docking of 49 in BRAF V600E (PDB ID: 3OG7). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 21. Development of ethynyl bridged pyrazolopyridine B-Raf^V600E inhibitor 49 from vemurafenib.

Fig. 22. (A) Development of pyrazolopyridine Syk inhibitor 51 from an indazole lead. (B) Molecular docking-based binding pose of 51 in Syk kinase (PDB ID: 3FQS). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 23. (A) Crystal structure of LOXO-292 in RET (PDB ID: 7JU6). (B) Chemical structure of LOXO-292 (selpercatinib). The hinge residues are illustrated in red, αC-helix residues in green and DFG motif in blue.

Fig. 24. (A) Optimization of compound 55. (B) Molecular docking-based binding pose of compound 55 in PI3Kγ (PDB ID: 3NZU). The hinge residues are illustrated in red and DFG motif in blue.

Fig. 25. (A) Chemical structure of camonsertib. (B) Chemical structure of olverembatinib. (C) Molecular docking of olverembatinib in the binding pocket of Abl1 kinase (PDB ID: 3QRI). The hinge residues are illustrated in red, αC-helix in pink and DFG motif in blue.