Author: Leonardi, Virginia ; Traver, David A. ; Truong, Anh P. ; Segales, Joshua S. ; Rassoulpour, Arash ; Ciaccio, Gillian L. ; Lewis, Colizel ; Wood, Stephen ; McDermott, Annie E. ; Kovalev, Sarah M. ; Molitor, Tyler P. ; Lin, Mei-Yao ; Bennett, Dylan S. ; Wong, Jamie K. ; Pei, Zhonghua ; Dani, Manjari ; Patel, Seona ; Sadiq, Saud A. ; Naphade, Swati ; Peterson, Nathan G. ; Akgungor, Zeynep ; Poston, Robert G. ; Dunn, Carissa J. ; Hayashi, Genki ; Kurnellas, Michael P.

GWAS have identified tyrosine kinase 2 (TYK2) variants in multiple inflammatory disorders, specifically a protective hypomorphic TYK2 allele (P1104A) in multiple sclerosis (MS). Impaired TYK2 signaling within the central nervous system (CNS) may impart the protective effects of TYK2 P1104A allele in MS. We deployed brain-penetrant TYK2 inhibitors (cTYK2i) alongside the peripherally restricted TYK2 inhibitor (pTYK2i; BMS-986165) to untangle the contributions of central TYK2 inhibition in diverse models of neuroinflammation. While pTYK2i had little impact, cTYK2i reduced clinical score, lymphoid cell infiltration, and cytokines/chemokines in experimental autoimmune encephalomyelitis (EAE). Microglial activation was attenuated in cTYK2i-treated EAE spinal cords and circulating neurofilament light (NfL) was reduced in plasma and cerebral spinal fluid (CSF). Additionally, cTYK2i was protective in an antibody-mediated mouse model of primary progressive MS (PPMS). Finally, we demonstrate TYK2 inhibition has a robust impact on a unique subset of activated astrocytes termed Interferon-Responsive-Reactive-Astrocytes (IRRA). The data presented herein identify a key role for CNS TYK2 signaling in regulating neuroinflammation and solidify TYK2 as a potential therapeutic target for MS.

01 Dec 2024·Cellular and Molecular Life Sciences

Macrophage re-programming by JAK inhibitors relies on MAFB

Article

Author: Torres-Torresano, Mónica ; López-Navarro, Baltasar ; Nieto-Valle, Alicia ; Castrejón, Isabel ; Simón-Fuentes, Miriam ; Ríos, Israel ; Puig-Kröger, Amaya ; Sanchez, Alicia ; Schiaffino, María Teresa

AbstractMonocyte-derived macrophages play a key pathogenic role in inflammatory diseases. In the case of rheumatoid arthritis (RA), the presence of specific synovial tissue-infiltrating macrophage subsets is associated with either active disease or inflammation resolution. JAK inhibitors (JAKi) are the first targeted synthetic disease-modifying antirheumatic drugs (tsDMARD) approved for treatment of RA with comparable efficacy to biologics. However, the effects of JAKi on macrophage specification and differentiation are currently unknown. We have analyzed the transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients and on the differentiation of monocyte-derived macrophages promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF), a factor that drives the development and pathogenesis of RA. We now report that JAKi Upadacitinib restores the balance of peripheral blood monocyte subsets in RA patients and skewed macrophages towards the acquisition of an anti-inflammatory transcriptional and functional profile in a dose-dependent manner. Upadacitinib-treated macrophages showed a strong positive enrichment of the genes that define synovial macrophages associated to homeostasis/inflammation resolution. Specifically, Upadacitinib-treated macrophages exhibited significantly elevated expression of MAFB and MAFB-regulated genes, elevated inhibitory phosphorylation of GSK3β, and higher phagocytic activity and showed an anti-inflammatory cytokine profile upon activation by pathogenic stimuli. These outcomes were also shared by macrophages exposed to other JAKi (baricitinib, tofacitinib), but not in the presence of the TYK2 inhibitor deucravacitinib. As a whole, our results indicate that JAKi promote macrophage re-programming towards the acquisition of a more anti-inflammatory/pro-resolution profile, an effect that correlates with the ability of JAKi to enhance MAFB expression.

28 Nov 2024·Journal of Medicinal Chemistry

Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent

Article

Author: Sridhar, Srikanth ; Dierks, Elizabeth A. ; Chiney, Manoj ; Yeshwante, Shekhar ; Mathur, Arvind ; A M Subbaiah, Murugaiah ; Desai, Salil ; Reddy, Maheswara ; Dierks, Elizabeth A ; Sivaprasad Lvj, Sankara ; Weinstein, David S. ; Moslin, Ryan ; Ramar, Thangeswaran ; Sivaprasad LVJ, Sankara ; Weinstein, David S

The pH-dependent solubility of the weakly basic TYK2 inhibitor 1 posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of 1 when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment. As part of risk mitigation, a prodrug strategy was explored by synthesizing solubility-enhancing prodrugs, resulting in the identification of lead prodrug 3c with acceptable stability and solubility profiles. In rats, the prodrug eliminated the significant difference in AUC and C_max between pentagastrin and famotidine arms, thereby effectively mitigating the impaired drug absorption at the elevated pH relevant for absorption and DDI with famotidine. The prodrug also facilitated dose-proportional systemic exposure of 1 following dose escalation in rats and monkeys.

100 Deals associated with TYK2 inhibitor(Neuron23)

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Sclerosis	Preclinical	United States	Neuron23, Inc.	30 Mar 2022
Inflammation	Preclinical	United States	origenis GmbH	01 Mar 2021

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