Clinical candidates of small molecule p38 MAPK inhibitors for inflammatory diseases

Abstract

The trigger and etiology of chronic inflammatory diseases are not well understood, hindering the development of efficient therapeutic approaches. The observation that abnormal activity of the p38 MAPK is common to all inflammatory diseases raised the expectation that p38 inhibitors would serve as general anti-inflammatory therapeutics. A large number of inhibitors were consequently discovered. Several compounds of different scaffolds, blocking the p38 MAPK signaling pathway, have entered phase II clinical trials for rheumatoid arthritis, chronic obstructive pulmonary disease, pain, cardiovascular diseases, and cancer. As I review here, in almost all cases the clinical trials have failed, leading to re-design of compounds and re-evaluation of p38 as a suitable target. I describe how structural features, unique to p38<span>α</span>, have been employed in the inhibitor design and achieved high degree of kinome selectivity. I then focus on some of the drugs that reached human trials and summarize their <em>in vitro/in vivo</em> pharmacological profiles and the related outcomes from clinical investigations. These compounds include VX-745, VX-702, RO-4402257, SCIO- 469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323 and GW-856553. Finally, I discuss novel suggested approaches for the use of p38 inhibitors such as combining p38 inhibition with inhibiting other targets that function in parallel inflammatory pathways for achieving efficacy in treating inflammatory diseases.

Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy

“…In this study, we demonstrated that DUX4 mRNA synthesis in FSHD myoblasts and myotubes is exquisitely sensitive to p38a/b inhibitors. The IC 50 vaues shown in Table I are in line with published activities determined for isolated p38a or p38b enzymes (Xing, 2015), strongly suggesting that DUX4 expression is positively regulated by p38a or p38 a/b kinase activity. One desirable characteristic of a drug intended for p38 Inhibitors Suppress DUX4 Expression in FSHD degenerative muscular dystrophy is that the treatment does not negatively affect the ability of muscle cells to participate in the muscle regenerative process.…”

“…One example of kinases that are activated by b2 adrenergic signaling in a protein kinase A-dependent manner is the set of p38 mitogen-activated protein kinases (MAPKs) (Moule and Denton, 1998;Zheng et al, 2000;Aggeli et al, 2002;McAlees and Sanders, 2009). The p38 MAPKs are classically involved in the cellular response to stressful stimuli, including inflammatory cytokines, and have been heavily pursued by pharmaceutical companies for diseases with inflammatory components, such as rheumatoid arthritis, resulting in an abundance of chemical tools from p38a selective to pan-p38 inhibitors (Xing, 2015). In exploring the hypothesis that activation of p38 plays a role in b2agonist repression of DUX4, we determined that rather than blocking the ability of b2-agonists to suppress DUX4, p38 inhibitors instead potently inhibit the expression of DUX4 in the absence of b2 agonism.…”

Invasive aspergillosis complicating treatment with tyrosine kinase inhibitors

“…The mitogen-activated protein kinase (MAPK) signalling pathway is involved in the pathophysiology of numerous cancers, including melanoma, leukaemia, pancreatic, colon, lung, biliary tract, salivary gland and thyroid carcinoma 1 2. As a consequence, tyrosine kinase inhibitors that lead to MAPK pathway inhibition are increasingly used in the treatment of malignant disease.…”

Recent advances in intra-articular drug delivery systems for osteoarthritis therapy

“…CNTX-4975 [32] SAR113945 [33] Sprifermin [34] Corticosterone [35] Methylprednisolone-acetate [36] Kondrium [37,38] Traumeel [39] Investigated small molecules for OA As described previously, OA has a complex pathophysiology that is not yet fully understood. Many pathways are involved in disease progression through the various tissues that constitute the joint.…”

“…study and the results of clinical Phase I appeared promising, but the Phase IIa study failed to show an effect in a larger patient sample size. Additionally, PH-797804, a potent p38 mitogen-activated protein kinase (MAPK) inhibitor, was investigated in a Phase II trial (NCT00620685) via oral administration in patients with rheumatoid arthritis but failed to demonstrate bioactivity after 2 weeks [35]. Another Phase II clinical trial (NCT01102660) is currently ongoing to examine knee-pain relief following the oral administration of PH-797804 versus naproxen in OA patients.…”