Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases

Abstract

Great successes have been achieved in developing small-molecule kinase inhibitors as anticancer therapeutic agents. However, kinase deregulation plays essential roles not only in cancer but also in almost all major disease areas. Accumulating evidence has revealed that kinases are promising drug targets for different diseases, including cancer, autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system disorders, viral infections, and malaria. Indeed, the first small-molecule kinase inhibitor for treatment of a nononcologic disease was approved in 2011 by the U.S. FDA. To date, 10 such inhibitors have been approved, and more are in clinical trials for applications other than cancer. This Perspective discusses a number of kinases and their small-molecule inhibitors for the treatment of diseases in nononcologic therapeutic fields. The opportunities and challenges in developing such inhibitors are also highlighted.

Host-directed therapy, an untapped opportunity for antimalarial intervention

“…The availability of pharmacokinetic and safety data will allow for careful delineation of dosing regimens to establish an appropriate therapeutic window. It is important to note that kinase inhibitors are not approved solely for cancer, and there is increasing interest in non-oncology indications, 73 , 74 reflecting the ability to design selective kinase inhibitors and the accumulating evidence that suitable safety margins for these molecules can be achieved in various contexts. In addition to the potential utility of approved medicines, it would also be of particular interest to identify compounds that passed early-phase clinical trials, and hence are supposedly tolerated enough for use in humans, but failed for efficacy against their original target indication.…”

Improved potency of pyridin-2(1H)one derivatives for the treatment of mechanical allodynia

“…The crude oil was purified by column chromatography (SiO2, cyclohexane to EtOAc/cyclohexane 3:97) to give 7 (69.0 mg, 0.161 mmol, 90%) as a white solid. Rf = 0.68 (EtOAc/cyclohexane 1:9); Mp 90 °C; IR (ATR) 3281, 1668, 1584, 1517, 1431, 1361, 1243, 1225, 736, -5-bromopyridin-3-yl)amino)benzoate (8) Compound 8 was prepared according to general procedure A, starting from 3 (199 mg, 0.713 mmol). The mixture was heated for 1 h 45 min.…”

“…Thus, numerous protein kinase inhibitors reached the market as anticancer drugs [5]. However, due to their pleiotropic role, protein kinases can be targeted for other application such as the treatment of pain [6][7][8]. It appears that some protein kinases are pivotal in the setting of central sensitization.…”

Outsmarting the Virus

“…This detail is now being unmasked through massive phosphoproteomics analyses which will form the basis for the targeting of susceptible critical points in kinase second messenger systems. 8 Among the most curious, long-lasting, and disruptive symptoms that can occur when the virus enters the human nervous system is the loss of smell and taste. This can be a persistent and difficult outcome to treat.…”