Targeting MAPAKAP2(MK2) to combat inflammation by avoiding the differential regulation of anti-inflammatory genes by p38 MAPK inhibitors

Abstract

ABSTRACTp38 mitogen-activated protein kinase (p38 MAPK) plays an important role in the key cellular processes related to inflammation. Several small molecule inhibitors of p38 MAPK therefore have been evaluated for their anti-inflammatory potential and progressed from early discovery to late phase clinical trials. Most of these efforts however have failed due to severe toxicity concerns. Since p38 MAPK has several downstream substrates, inhibition of p38 MAPK, therefore, leads to the modulation of all its substrates, resulting into a dis-balance of pro- and anti-inflammatory response and multiple toxicity concerns. Targeting p38MAPK MAPKAPK2 (MK2), one of the downstream substrates of p38 MAPK directly, is expected to be a better anti-inflammatory approach without having any toxicity concerns. In this manuscript, we are reporting biological data of representative MK2 inhibitor to validate its anti-inflammatory potential and a comparison of p38 MAPK and MK2 inhibitors in cell based assays to understand their relative toxicities.

Revisiting p38 Mitogen-Activated Protein Kinases (MAPK) in Inflammatory Arthritis: A Narrative of the Emergence of MAPK-Activated Protein Kinase Inhibitors (MK2i)

“…A phase I placebo-controlled study of an MK2 inhibitor by Gordon et al observed that the drug (ATI-450) was well tolerated with minor side effects, which supported its further investigation in inflammatory diseases [ 84 ]. Singh and colleagues compared the p38-MAPK inhibitors SB-203580 and BIRB-796 with MK2i PF-3644022 toxicity profiles and mechanism of action in vitro and in vivo [ 85 ]. They found that while both p38 and MK2 inhibitors exhibited strong anti-inflammatory properties by potently inhibiting levels of LPS-induced TNFα and IL-6 in human peripheral blood mononuclear cells (PBMCs), nuances were evident in their inhibitory profiles that would impact their anti-inflammatory potential.…”

“…They found that while both p38 and MK2 inhibitors exhibited strong anti-inflammatory properties by potently inhibiting levels of LPS-induced TNFα and IL-6 in human peripheral blood mononuclear cells (PBMCs), nuances were evident in their inhibitory profiles that would impact their anti-inflammatory potential. They outlined that BIRB-796 (the p38-MAPK inhibitor) led to a decrease in phosphorylation of mitogen- and stress-activated kinases (Msk1/2) with reduction of the anti-inflammatory cytokine IL-10 in the LPS-treated PBMCs [ 85 ]. However, this was not the case with PF-3644022 (the MK2i), which maintained the production of the anti-inflammatory cytokine IL-10 and indicated a dose-dependent reduction of IL-6.…”

“…However, this was not the case with PF-3644022 (the MK2i), which maintained the production of the anti-inflammatory cytokine IL-10 and indicated a dose-dependent reduction of IL-6. Additionally, evidence suggesting that MK2i would display lesser toxicity by avoiding participating in the feedback signaling loop and not activating the JNK pathway, potentially preventing tachyphylaxis was observed [ 85 ].…”

“…There have been reports outlining certain challenges faced by the first generation of ATP-competitive MK2 inhibitors. These include low solubility, poor cell permeability, and insufficient kinase selectivity [ 85 ]. During the process of manuscript finalization, a report emerged of a phase 2 study of the MK2i CC-99677 that was being investigated by BMS [ 89 ].…”