A comprehensive review of protein kinase inhibitors for cancer therapy

Abstract

Protein kinases are involved in various cellular functions. About 2% of the human genome encodes for protein kinases. Dysregulation of protein kinases is implicated in various processes of carcinogenesis. The advent of protein kinase inhibitors in cancer therapy has led to a paradigm shift in cancer therapy. Several protein kinase inhibitors have been approved by FDA in the last few decades. Areas covered: This article provides a review of the FDA approved protein kinase inhibitors as of December 2017 for the well-known oncogenic protein kinases. A list of FDA approved protein kinase inhibitors and their FDA approved clinical indications were cataloged. The role of the respective oncogenic protein kinases in carcinogenesis and cancer progression and the relevant landmark clinical trials of respective protein kinase inhibitors leading up to the FDA approval were PubMed searched and discussed. Expert commentary: Further understanding of the molecular origin of various cancers would help identify new targets. Use of biomarker profiling might select the patient population that would benefit better from kinase inhibitors. Clinical trials should be designed to identify the appropriate sequence of the available kinase inhibitors. It would prove to be useful to test these drugs in the adjuvant setting.

Keywords: Cancer therapy; kinase inhibitors; medicinal chemistry; targeted therapy; tyrosine kinase inhibitors.

Figure 1:

The ‘Human Kinome’ as adapted from ‘ The Protein Kinase Complement of the Human Genome’ [2]. Human kinome represented as a phylogenetic tree listed in the scientific database. In addition to the eight protein kinase groups depicted in the main dendrogram, lipid, atypical and clinically-relevant mutant kinases are also annotated to the human kinome. The classic kinase dendrogram includes the following eight kinase groups: TK - Tyrosine kinase; TKL - Tyrosine kinase-like; STE - Homologs of yeast Sterile 7, Sterile 11, Sterile kinases; CK1 - Casein kinase 1; AGC - Containing PKA, PKG, PKC families; CAMK - Calcium/calmodulin-dependent protein kinase; CMGC - Containing CDK, MAPK, GSK3, CLK families; OTHER - Divergent kinases not represented in other groups.

Figure 2:

The phylogenetic map of the human kinome demonstrating development and US FDA approval of small molecule kinase inhibitors to tyrosine kinases and serine/threonine kinases for a variety of solid and hematologic malignancies. Other kinome family members under active clinical investigation include NTRK-fusion activated kinase, CDK8, and ERK1/2.

Figure 3:

Chemical structure of a prototype TKI imatinib as adapted from National Center for Biotechnology Information.

Figure 4:

Chemical structure of an EGFR KI inhibitor gefitinib as adapted from National Center for Biotechnology Information.

Figure 5:

Chemical structure of a serine/threonine kinase inhibitor vemurafenib as adapted from National Center for Biotechnology Information.