PD 198306

IC50: 8 nM for MEK [1]

PD 198306 is a potent, selective and non-ATP competitive MAPK/ERK-kinase (MEK) inhibitor. MEK is a kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).

In vitro: PD 198306 inhibits the isolated MEK at a concentration of 8 nM and inhibits MEK activity in synovial fibroblasts at 30–100 nM, depending on the species. PD 198306 is highly selective for MEK and has a IC50 of >4 uM for c-Src, >1 uM for ERK, >4 uM for cyclin-dependent kinases and >10 uM for phosphatidylinositol 3-kinase [1].

In vivo: Rabbits treated with PD 198306 showd a significant dose-dependent reduction in the level of phospho-ERK-1/2 and a lower level of MMP-1. PD 198306 can partially decrease the development of some of the structural changes in experimental rabbit model of osteoarthritis [1]. PD 198306 dose-dependently blocked static allodynia in both the streptozocin and the chronic constriction injury models of neuropathic pain. These antihyperalgesic effects correlated with a reduction in the elevated levels of active ERK1 and 2 in lumbar spinal cord [2].

Clinical trial: So far, no clinical study has been conducted.

References:
[1] Pelletier JP, Fernandes JC, Brunet J, Moldovan F, Schrier D, Flory C, Martel-Pelletier J.  In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes. Arthritis Rheum. 2003 Jun;48(6):1582-93.
[2] Ciruela A, Dixon AK, Bramwell S, Gonzalez MI, Pinnock RD, Lee K.  Identification of MEK1 as a novel target for the treatment of neuropathic pain. Br J Pharmacol. 2003 Mar;138(5):751-6.

Co-expression of AFAP1-AS1 and PD-1 predicts poor prognosis in nasopharyngeal carcinoma.[Pubmed:28380458]

Oncotarget. 2017 Jun 13;8(24):39001-39011.

Nasopharyngeal carcinoma (NPC) carries a high potential for metastasis and immune escape, with a great risk of relapse after primary treatment. Through analysis of whole genome expression profiling data in NPC samples, we found that the expression of a long non-coding RNA (lncRNA), actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1), is significantly correlated with the immune escape marker programmed death 1 (PD-1). We therefore assessed the expression of AFAP1-AS1 and PD-1 in a cohort of 96 paraffin-embedded NPC samples and confirmed that AFAP1-AS1 and PD-1 are co-expressed in infiltrating lymphocytes in NPC tissue. Moreover, patients with high expression of AFAP1-AS1 or PD-1 in infiltrating lymphocytes were more prone to distant metastasis, and NPC patients with positive expression of both AFAP1-AS1 and PD-1 had the poorest prognosis. This study suggests that AFAP1-AS1 and PD-1 may be potential therapeutic targets in NPC and that patients with co-expression of AFAP1-AS1 and PD-1 may be ideal candidates for future clinical trials of anti-PD-1 immune therapy.

Mechanistic insight into the regioselectivity of Pd(ii)-catalyzed C-H functionalization of N-methoxy cinnamamide.[Pubmed:28379232]

Dalton Trans. 2017 Apr 19;46(16):5288-5296.

Computational studies have been applied to gain insight into the mechanism of Pd(ii) catalyzed alpha-C-H functionalization of N-methoxy cinnamamide. The results show that the whole catalytic cycle proceeds via sequential six steps, including (i) catalyst Pd(t-BuNC)2 oxidation with O2, (ii) O-H deprotonation, (iii) t-BuNC migratory insertion to the Pd-C bond, (iv) acyl migration, (v) C-H activation and (vi) reductive elimination. The regioselectivity for different C-H activation sites depends on the coordination structures of alpha-C or beta-C to the palladium(ii) center. The coordination of alpha-C to the palladium(ii) center shows a regular planar quadrilateral structure, which is stable. However, the beta-C coordinating to the palladium(ii) center mainly exhibits a distorted quadrilateral structure, which is relatively unstable. Thus, the barrier of alpha-C-H activation is much lower than that of beta-C-H activation. The present results provide a deep understanding of the site-selectivity of C-H activation.

Three 1D cyanide-bridged M(Ni, Pd, Pt)-Mn(II) Coordination Polymer: Synthesis, Crystal Structure and Magnetic Properties.[Pubmed:28380238]

Acta Chim Slov. 2017 Mac;64(1):215-220.

Three tetracyanide-containing building blocks K2[M(CN)4] (M = Ni, Pd, Pt) and one semi-closed macrocycle seven-coordinated manganese(II) compound have been employed to assemble cyanide-bridged heterometallic complexes, resulting in three cyanide-bridged MII-MnII complexes: [Mn(L)][Ni(CN)4] . 2H2O (1) [Mn(L)][Pd(CN)4] (2) and [Mn(L)][Pt(CN)4] (3) (L = 2,6-bis[1-(2-(N-methylamino)ethylimino)ethyl]pyridine). Single-crystal X-ray diffraction analysis shows their similar one-dimensional structure consisting of the alternating [Mn(L)]2+ species and [M(CN)4]2- building blocks, generating a cyanide-bridged neutral polymeric chain. In all three isostructural complexes the coordination geometry of manganese ion is a slightly distorted pentagonal-bipyramidal with the two cyanide nitrogen atoms at the trans positions and N5 coordinating mode at the equatorial plane from ligand L. Investigation over magnetic properties of these complexes reveals very weak antiferromagnetic interaction between neighboring Mn(II) ions bridged by the long NC-M-CN unit. A best-fit to the magnetic susceptibility of complexes 1-3 leads to the magnetic coupling constant of J = -0.081, -0.103 and -0.14 cm-1, respectively.

Pd-Catalyzed Autotandem Reactions with N-Tosylhydrazones. Synthesis of Condensed Carbo- and Heterocycles by Formation of a C-C Single Bond and a C horizontal lineC Double Bond on the Same Carbon Atom.[Pubmed:28379703]

Org Lett. 2017 Apr 21;19(8):2034-2037.

A new Pd-catalyzed autotandem reaction is introduced that consists of the cross-coupling of a benzyl bromide with a N-tosylhydrazone followed by an intramolecular Heck reaction with an aryl bromide. During the process, a single and a double C-C bond are formed on the same carbon atom. Two different arrangements for the reactive functional groups are possible, rendering great flexibility to the transformation. The same strategy led to 9-methylene-9H-fluorenes, 9-methylene-9H-xanthenes, 9-methylene-9,10-dihydroacridines, and also dihydropyrroloisoquinoline and dihydroindoloisoquinoline derivatives.

Identification of MEK1 as a novel target for the treatment of neuropathic pain.[Pubmed:12642375]

Br J Pharmacol. 2003 Mar;138(5):751-6.

(1) In the present study we have attempted to identify changes in gene expression which are associated with neuropathic pain using subtractive suppression hybridization analysis of the lumbar spinal cord of animals suffering streptozocin induced diabetic neuropathy. (2) Using this approach, we found a significant up-regulation of several key components of the extracellular signal-regulated kinase (ERK) cascade. These findings were confirmed by Western blot analysis, which demonstrated that the levels of active ERK1 and 2 correlated with the onset of streptozocin-induced hyperalgesia. (3) Intrathecal administration of the selective MAPK/ERK-kinase (MEK) inhibitor PD 198306 dose-dependently (1-30 micro g) blocked static allodynia in both the streptozocin and the chronic constriction injury (CCI) models of neuropathic pain. (4) The antihyperalgesic effects of PD 198306, in both the streptozocin and CCI models of neuropathic pain, correlated with a reduction in the elevated levels of active ERK1 and 2 in lumbar spinal cord. (5) Intraplantar administration of PD 198306 had no effect in either model of hyperalgesia, indicating that changes in the activation of ERKs and the effect of MEK inhibition are localized to the central nervous system. (6) In summary, we have demonstrated for the first time that the development of neuropathic pain is associated with an increase in the activity of the MAPK/ERK-kinase cascade within the spinal cord and that enzymes in this pathway represent potential targets for the treatment of this condition.