Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Abstract

The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

A Comprehensive Overview of Globally Approved JAK Inhibitors

“…The synthesis of filgotinib ( Scheme 8 ) was achieved in a five-step synthesis [ 114 , 115 ]. Initially, compound 64 was reacted with thiomorpholine 1,1-dioxide 65 to give 66 .…”

“…The synthesis of ruxolitinib ( Scheme 12 ) was achieved from compound 12 in a five-step synthesis [ 115 , 161 ]. Compound 12 was first reacted with 2-(trimethylsilyl)ethoxyethyl chloride (SEM-Cl) to give 24 .…”

“…Tofacitinib ( Figure 58 ) is a JAK inhibitor that was approved by the FDA for rheumatoid arthritis in 2012 [ 64 , 177 , 178 ]. It was also approved for the treatment of psoriatic arthritis and ulcerative colitis in 2017 and 2018, respectively [ 115 ]. In addition, tofacitinib has received FDA approval for the treatment of juvenile idiopathic arthritis in 2020 [ 179 ].…”

Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review

“…Currently, one of the most important modalities for cancer treatment is the targeted therapy which hampers the growth of cancer cells by chemical intervention against specific target biomolecules known to be essential for tumorigenesis and proliferation. A number of protein kinases in the human body are associated with cancer initiation and progression, and small molecules that inhibit these kinases have thus far gained notable achievement manifested by ∼70 FDA-approved small molecule kinase inhibitor drugs for the treatment of a variety of malignancies ( Ayala-Aguilera et al, 2022 ). FGFRs are a family of receptor tyrosine kinases that have been successfully targeted by three approved small-molecule inhibitors.…”

Regulatory spine RS3 residue of protein kinases: a lipophilic bystander or a decisive element in the small-molecule kinase inhibitor binding?

“…According to the Protein Kinase Inhibitors in Clinical Trials database (PKIDB) [14,15], approximately 300 small-molecule kinase inhibitors are either in clinical trials or already approved. Comprehensive reviews of the kinase inhibitor drug discovery and kinase inhibitor development are available [16][17][18]. Currently, oncology is dominating indication for the kinase inhibitors, but there is potential also in other therapeutic areas such as autoimmune and inflammatory diseases, and degenerative disorders [19].…”