Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

Abstract

The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR–Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.

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

“…was obtained as an orange solid. Rf = 0.35 (CH2Cl2/MeOH 98:2 + 0.5% NEt3); Mp > 263 °C (decomposition); IR (ATR) 3285,1680,1654,1627,1452,1238, 750 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.79 (br s, 1H), 11.13 (s,1H),8.88 (s,1H),7.87 (dd,J1 = 8.1 Hz,J2 = 1.7 Hz,1H),7.51 (d,J = 3.0 Hz,1H),2H),7.36 (dt, J = 8.1 Hz, J2 = 0.9 Hz, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.26 (dd, J1 = 7.4 Hz, J2 = 0.9 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 6.82 (dd, J1 = 8.6 Hz, J2 = 0.9 Hz, 1H), 6.72 (ddd, J1 = 8.2 Hz, J2 = 7.2 Hz, J3 = 1.2 Hz, 1H), 6.38-6.35 (m, 1H)…”

“…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.…”

“…756 cm -1 ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 11.44 (br s, 1H),11.13 (s, 1H), 7.49 (d, J = 3.0 Hz, 1H), 2H), 7.25 (d, J = 7.3 Hz, 1H), 7.19 (s, 1H),7.09 (br s, 1H), 7.09 (t, J = 7.7 Hz, 1H),6.83-6.76 (m, 4H), 6.36-6.34 (m, 1H), 3.66 (s, 3H); 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 159.3 (C=O), 152.5 (C), 139.7 (C), 137.2 (CH), 136.1 (C), 130.5 (C), 128.5 (C), 126.1 (C), 125.3 (CH), 124.6 (C), 124.0 (CH), 120.4 (CH), 119.9 (CH), 116.5 (2CH), 114.7 (2CH), 110.8 (CH), 100.6 (CH), 55.3 (CH3); HRMS (ESI+) calcd for C20H18N3O2 (M+H) + 332.1394, found 332.1398; HPLC purity ≥ 96%, tR = 7.71 min, λ = 280 nm. (CH), 136.1 (C), 131.1 (C), 130.5 (CH), 129.1 (CH), 128.1 (C), 126.1 (C), 125.4 (CH), 120.5 (C), 120.4 (CH), 120.0 (CH), 119.7 (CH), 111.8 (CH), 111.0 (CH), 106.6 (CH), 100.4 (CH); HRMS (ESI+) calcd for C19H15N4O3 (M+H) + 347.1139, found 347.1140; HPLC purity ≥ 95%, tR = 7.92 min, λ = 260 nm.…”

Synthesis and Kinase Inhibitory Potencies of Pyrazolo[3,4-g]isoquinolines

“…Protein kinases are implicated in cellular signaling pathways involved in various pathologies such as cancer, neurodegenerative disorders or pain [ 1 ]. Therefore, these transferases, able to modulate protein targets by transferring a γ-ATP phosphate group to Ser/Thr and/or Tyr residues, are key targets for identifying new therapeutic strategies.…”

Corydalis saxicola Bunting total alkaloids attenuate paclitaxel-induced peripheral neuropathy through PKCε/p38 MAPK/TRPV1 signaling pathway

“…MAPK family is a class of highly conserved serine/threonine protein kinases, while MAPK is mediated by p38 rather than ERK in the pathogenesis of pain [ 16 ]. p38 MAPK, as a tyrosine phosphoprotein kinase, is activated by stress signals and inflammatory stimuli and contributes to cellular responses associated with neuropathic pain [ 17 , 18 ]. Activation of p38 MAPK in DRG can increase translation and transport of TRPV1 to the terminal of the peripheral nociceptor, contributing to the maintenance of thermal hyperalgesia [ 16 ].…”