Myelofibrosis (MF) is a hematopoietic disorder featuring
JAK2 pathway dysregulation, leading to symptoms like
splenomegaly. While
ruxolitinib can alleviate these symptoms, treatment is often constrained by loss of efficacy, adverse effects, and disease progression. There is an unmet need for novel therapies that can modify the disease course.
TL-895 is an orally available small molecule inhibitor of
BTK and
BMX, currently under investigation for its potential to impede abnormal cell adhesion and trafficking in
MF patients, ameliorate cytokine-driven symptoms, and enhance megakaryopoiesis.
The study aimed to evaluate TL-895's impact on signaling, cell adhesion, and chemotaxis in JAK2VF cells. Cells expressing JAK2WT and JAK2VF were treated with TL-895,
ibrutinib, or ruxolitinib, and intracellular signaling was assessed. Adhesion assays on ICAM or VCAM-coated plates and trans-well motility assays using SDF1α as a chemo-attractant were conducted.
RAC1 activation was measured to understand its role in cell movement.
The results indicated that TL-895 effectively reduced BTK pathway activation in JAK2VF cells. It also significantly blocked cell adhesion on VCAM and ICAM surfaces and inhibited chemotaxis toward SDF1α. Additionally, TL-895 treatment decreased RAC1 activation, suggesting its role in influencing cell adhesion and movement.
The study concludes that TL-895's inhibition of BTK signaling could disrupt the interaction of JAK2VF myeloblasts with the microenvironment, potentially improving MF patient outcomes. Clinical trials are underway to test this hypothesis.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
