Janus Kinase Inhibitor R&D for IBD

Janus kinases (JAK) are a family of cytoplasmatic tyrosine kinases, including JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) that, after stimulation of cells with cytokines, activate the transcription factor activator of transcription (STAT) pathway to transmit signals into cells. JAKs are indispensable in innate immunity, adaptive immunity and haematopoiesis, and they are involved in normal cellular functions such as proliferation, survival, differentiation and migration. The pathogenic mechanisms in both UC and CD are shared in many aspects, which includes a dysregulated JAK pathway. Dysregulated JAK-STAT activation could therefore provide an ideal therapeutic target for IBD.

Fig. 1. The structure of a janus kinase (JAK) protein and the mechanism of action of JAK inhibitors. Fig. 1. The structure of a JAK protein and the mechanism of action of JAK inhibitors. (Honap, et al., 2024)

Janus Kinase Inhibitor R&D Services

Ace Therapeutics is a contract research organization specializing in developing JAK inhibitors for IBD. Ace Therapeutics have dedicated ourselves to solving the problem and totally concentrate on pharmaceuticals for the purpose of helping all types of pharmaceuticals companies to make better medicines to cure IBD, covering preclinical study to efficacy/safety validation, our medicinal chemists also capable of building new molecule drugs, especially preclinical development of JAK inhibitors for IBD.

Design and Development of JAK Inhibitors for IBD

With our advanced capabilities in structure-guided drug design, we empower our clients to optimize the selectivity and efficacy of JAK inhibitors for IBD. We specialize in the design of JAK inhibitors by:

Together with our clients, we utilize our cutting-edge structure-guided drug design expertise to refine the selectivity and efficacy of JAK inhibitors for IBD. We design JAK inhibitors by:

Targeting the JAK-STAT signaling pathway to minimize off-target effects.
Modifying chemical scaffolds to increase binding affinity and selectivity.
Optimizing lead compounds through structure-activity relationship (SAR) studies.

To do this, we use computational modelling, homology modelling and innovative cocrystal structures of JAK proteins and their inhibitors to accommodate our clients.

Computational modeling	We use sophisticated computational modeling techniques to predict interactions between JAK proteins and potential inhibitors. Molecular docking: Simulating how small molecules bind to JAK proteins to identify promising candidate proteins. Molecular dynamics simulations: Assessing the stability and behavior of protein-ligand complexes over time to improve inhibitor design.
Homology modeling	We can confidently generate accurate 3D models of the experimental structures using the homology modelling technique based on known structures. On this base, if there are no experimental structures available, we could use homology modelling to generate highly accurate 3D models for our clients. This way, we may assist the clients in the ligand-target identification due to the pinpoint identification of the binding sites and their residues in the JAK proteins.
New JAK protein and inhibitor co-crystal structures	By characterizing new JAK protein and inhibitor co-crystal structures, we can then walk our clients through these interactions at the atomic level, and identify the key features of new inhibitors that render them better selective and potent than their previous compounds.

Evalaution of the Efficacy and Safety of JAK Inhibitors in IBD

We offer different colitis animal models (eg, DSS-induced colitis model and TNBS-induced colitis model) to comprehensively assess the safety and effectiveness of JAK inhibitors, to provide valuable basic data for subsequent drug development.

Scores of IBD severity using a combination of measure of parameters such as stool blood, weight loss and activity level.
We then slice and stain colon tissues, helping to pinpoint whether the tissues are damaged, and by what degree.
IL-6 and TNF-α are inflammatory mediators that can be measured and help to demonstrate that the impact of JAK inhibitors is anti-inflammatory.
Structural gut dysfunction (e.g., disorganization and changes to the gut integrity) can be measured with imaging (e.g., using ultrasound or magnetic resonance imaging [MRI]).
We conduct toxicity studies to evaluate the safety profile of JAK inhibitors.

Ace Therapeutics aims at developing JAK inhibitors for clients through the targeted joining of proteins/ligands to key components of JAK-STAT signaling pathways to effectively treat IBD. To get in touch with us if you're interested in our services.

Reference

Honap, S., et al. (2024). JAK inhibitors for inflammatory bowel disease: recent advances. Frontline Gastroenterology, 15(1), 59-69.

! For research use only, not intended for any clinical use.