Therapeutics

MW150

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Overview

Name: MW150
Synonyms: MW01-18-150SRM
Chemical Name: 6-(4-methylpiperazin-1-yl)-3-naphthalen-2-yl-4-pyridin-4-ylpyridazine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Neurokine Therapeutics

Background

MW150 is a CNS-penetrant, selective inhibitor of the alpha isoform of the mitogen-activated serine/threonine protein kinase p38 MAPK. It is taken by mouth.

p38α MAPK is expressed in microglia and neurons. In microglia, the enzyme stimulates release of pro-inflammatory cytokines such as TNFα and IL-1β in response to a variety of stressors including Aβ42; in neurons, signaling via p38α MAPK has been implicated in tau localization and neuronal plasticity (Yasuda et al., 2011; Bachstetter et al., 2011; Corrêa and Eales, 2012). In addition, p38α MAPK regulates Ras-related protein Rab5, a key regulator of early endosomes whose role in endolysosomal and synaptic vesicle function has made it a target in neurodegenerative disease drug development (Germann and Alam, 2020).

MW150 is one of a series of compounds co-developed by investigators at Northwestern University in Chicago and Columbia University in New York (Jan 2002 news; May 2017 conference news; Jun 2018 conference news).

For MW150, a kinase inhibitor fragment was built out to achieve isoform specificity and brain penetration. In the APP/PS1 mouse model of amyloidosis, treatment from an early age prevented the development of memory deficits, without affecting amyloid plaque accumulation. In APP/PS knock-in mice, treatment of older mice suppressed memory deficits (Roy et al., 2015; Roy et al., 2019). MW150 inhibited the release of proinflammatory cytokines from glia, and rescued synaptic dysfunction in the entorhinal cortex of these models (Zhou et al., 2017; Rutigliano et al., 2018).

In a mouse model of autism spectrum disorder, MW150 normalized poor social behaviors and physiological disturbances stemming from excess serotonin activity (Robson et al., 2018).

A related preclinical p38MAPKα inhibitor, MW181, was reported to reduce tau pathology in a mouse model of tauopathy (Maphis et al., 2016).

Findings

In 2018, the Alzheimer’s Association funded a Phase 1 study of MW150. According to information on the company’s web site, the drug was safe, well-tolerated, and reached promising blood levels after daily oral administration to healthy volunteers.

In January 2022, the company listed a Phase 2 study in people with mild to moderate AD. Beginning in May 2022, the 24 participants will take one 10 mg capsule of MW150 or placebo daily for 12 weeks. Primary outcomes are safety and adverse events. Secondary outcomes include measures of cognition, daily function, neuropsychiatric symptoms, and blood levels of cytokines, tau, and neurofilament light. The trial is expected to run until August 2024.

MW150 is one of two p38α MAPK inhibitors in development for Alzheimer’s; the other is neflamapimod.

For details on MW150 trials, see clinicaltrials.gov.

Last Updated: 13 May 2022

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References

Therapeutics Citations

  1. Neflamapimod

News Citations

  1. Targeting Glial Cells—Towards Selective, CNS-Specific Antiinflammatory Drugs
  2. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration
  3. NIH Summit Wraps Up with Recommendations for Research

Paper Citations

  1. Yasuda S, Sugiura H, Tanaka H, Takigami S, Yamagata K. p38 MAP kinase inhibitors as potential therapeutic drugs for neural diseases. Cent Nerv Syst Agents Med Chem. 2011 Mar 1;11(1):45-59. PubMed.
  2. Bachstetter AD, Xing B, de Almeida L, Dimayuga ER, Watterson DM, Van Eldik LJ. Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ). J Neuroinflammation. 2011;8:79. PubMed.
  3. Corrêa SA, Eales KL. The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease. J Signal Transduct. 2012;2012:649079. PubMed.
  4. Germann UA, Alam JJ. P38α MAPK Signaling-A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease. Int J Mol Sci. 2020 Jul 31;21(15) PubMed.
  5. Roy SM, Grum-Tokars VL, Schavocky JP, Saeed F, Staniszewski A, Teich AF, Arancio O, Bachstetter AD, Webster SJ, Van Eldik LJ, Minasov G, Anderson WF, Pelletier JC, Watterson DM. Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models. ACS Chem Neurosci. 2015 Apr 15;6(4):666-80. Epub 2015 Feb 23 PubMed.
  6. Roy SM, Minasov G, Arancio O, Chico LW, Van Eldik LJ, Anderson WF, Pelletier JC, Watterson DM. A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction. J Med Chem. 2019 Jun 13;62(11):5298-5311. Epub 2019 Apr 23 PubMed.
  7. Zhou Z, Bachstetter AD, Späni CB, Roy SM, Watterson DM, Van Eldik LJ. Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes. J Neuroinflammation. 2017 Apr 5;14(1):75. PubMed.
  8. Rutigliano G, Stazi M, Arancio O, Watterson DM, Origlia N. An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease. Neurobiol Aging. 2018 Oct;70:86-91. Epub 2018 Jun 12 PubMed.
  9. Robson MJ, Quinlan MA, Margolis KG, Gajewski-Kurdziel PA, Veenstra-VanderWeele J, Gershon MD, Watterson DM, Blakely RD. p38α MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10245-E10254. Epub 2018 Oct 8 PubMed.
  10. Maphis N, Jiang S, Xu G, Kokiko-Cochran ON, Roy SM, Van Eldik LJ, Watterson DM, Lamb BT, Bhaskar K. Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther. 2016 Dec 15;8(1):54. PubMed.

External Citations

  1. company’s web site
  2. clinicaltrials.gov

Further Reading

Papers

  1. Kheiri G, Dolatshahi M, Rahmani F, Rezaei N. Role of p38/MAPKs in Alzheimer's disease: implications for amyloid beta toxicity targeted therapy. Rev Neurosci. 2018 May 28; PubMed.
  2. Growcott EJ, Bamba D, Galarneau JR, Leonard VH, Schul W, Stein D, Osborne CS. The effect of P38 MAP kinase inhibition in a mouse model of influenza. J Med Microbiol. 2018 Mar;67(3):452-462. Epub 2018 Jan 24 PubMed.
  3. Chen K, Lu Y, Liu C, Zhang L, Fang Z, Yu G. Morroniside prevents H2 O2 or Aβ1-42 -induced apoptosis via attenuating JNK and p38 MAPK phosphorylation. Eur J Pharmacol. 2018 Sep 5;834:295-304. Epub 2018 Jul 27 PubMed.