Kinase-targeted cancer therapies: progress, challenges and future directions

Abstract

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

Keywords: Cancer; Kinase inhibition; Kinases; Oncology; Small-molecule drugs.

Fig. 1

Chemical structures of representative kinase inhibitors used for treatment of various human cancers

Fig. 2

Categorization of different kinases implicated in human cancer. CTK: cytoplasmic tyrosine kinase, S/T Kinase: serine/threonine kinase, LK: lipid kinase, RTK: receptor tyrosine kinase. SK1: Sphingosine kinase 1, PI3K: phosphoinositide 3-kinase, PKCi: Protein kinase Ci, mTOR: mammalian target of rapamycin, CDKs: cyclin-dependent kinases, ATM: Ataxia telangiectasia mutated, Akt: protein kinase B, S6K: ribosomal protein S6 kinase, STK11/LKB1: Serine/threonine kinase 11 or liver kinase B1, PLKs: Polo-like kinases, b-Raf: B-Raf proto-oncogene, Aur A & B: Aurora Kinase A & B, c-SRC: Proto-oncogene tyrosine-protein kinase Src, c-YES: c-Yes proto-oncogene (pp62c-Yes), Abl: Abelson murine leukemia viral oncogene homolog 1, JAK-2: Janus kinase 2, RON: Recepteur d’Origine Nantais, FGFRs: Fibroblast growth factor receptors, c-Met: c-MET proto-oncogene, c-Ret: c-RET proto-oncogene, IGF-IR: Insulin-like growth factor 1 receptor, EGFR: Epidermal growth factor receptor, PDGFR-α: Platelet-derived growth factor receptor α, c-Kit: proto-oncogene c-Kit or Mast/stem cell growth factor receptor, Flt3,Flt-4: Fms-like tyrosine kinase 3, 4, PDGFR-β: Platelet-derived growth factor receptor β, ALK: Anaplastic lymphoma kinase, HER-2: human epidermal growth factor receptor-2

Fig. 3

Timeline of key events in the development of protein-kinase inhibitors for the treatment of cancer

Fig. 4

Interruption of the BCR-Abl pathway can be achieved by Gleevec (imatinib mesylate)

Fig. 5

Structures of key natural bioactives which pharmacologically modulate kinases